Cysteine derivative

ABSTRACT

Cysteine compounds represented by the following formula 
                         
wherein each symbol is as defined in the specification, and salts thereof, are superior in stability, have less odor, exhibit an eumelanin production suppressive effect, and are useful as cosmetic agents.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.13/686,384, filed on Nov. 27, 2012, which is a continuation ofInternational Patent Application No. PCT/JP2011/062293, filed on May 27,2011, and claims priority to Japanese Patent Application No.2010-123169, filed on May 28, 2010, each of which are incorporatedherein by reference in their entireties.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to particular cysteine derivatives.Furthermore, the present invention relates to methods for producingparticular cysteine derivatives, cosmetic agents which containparticular cysteine derivatives, and the like.

Discussion of the Background

In human pigment cells (melanocytes) in the skin, melanin is producedutilizing L-cysteine and L-tyrosine. When a greater amount ofL-tyrosine, which is a starting material for eumelanin, is utilized forthe synthesis of melanin, production of eumelanin is promoted and theskin becomes dark. On the other hand, when a greater amount ofL-cysteine is utilized for the synthesis of melanin, production ofeumelanin is suppressed, and the skin becomes closer to yellow.Therefore, it is considered that production of eumelanin is suppressedby supplying L-cysteine during melanin synthesis.

Heretofore, many attempts have been made to utilize L-cysteine ascosmetics such as whitening agents utilizing L-cysteine and the like.However, L-cysteine is easily oxidized, and has problems such as poorstability and bad odor for formulating as a cosmetic agent or skinexternal preparation.

To solve such problem, the development of a cysteine derivative withimproved stability has been considered. JP-B-48-15938 discloses thatL-2-methylthiazolidine-2,4-dicarboxylic acid is extremely stable ascompared to conventional cysteine derivatives.

In addition, JP-A-2009-227660 discloses that a cysteine derivativeobtained by esterification of L-2-methylthiazolidine-2,4-dicarboxylicacid or a salt thereof is useful as a whitening agent etc. since it hasan eumelanin production suppressive effect and is stable. Furthermore,JP-A-2010-1239 discloses that 2-methylthiazolidine-2,4-dicarboxylic acidor a derivative thereof has a whitening action.

On the other hand, J. Biological Chem., (1937) 121 539-48 disclosesN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid andN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid anhydride; however,it does not describe their properties such as stability etc. andphysiological activities thereof, nor does it suggest or report use forcosmetic agents or skin external preparations or whitening effectsthereof.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide novelcysteine derivatives.

It is another object of the present invention to provide novel cysteinederivatives having an eumelanin production suppressive effect.

It is another object of the present invention to provide novel cysteinederivatives which exhibit superior stability.

It is another object of the present invention to provide novel cysteinederivatives which have less odor.

It is another object of the present invention to provide novel methodsfor producing such a cysteine derivative.

It is another object of the present invention to provide novel cosmeticagents which contain such a cysteine derivative.

It is another object of the present invention to provide novel cosmeticcompositions which are superior in long-term preservation stability.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat particular cysteine derivatives are particularly superior in thestability, have less odor, and show a sufficient eumelanin productionsuppressive effect in a cell assay.

Accordingly, the present invention provides the following:

(1) A cosmetic agent, comprising a cysteine derivative represented byformula (I):

wherein

X and Y are each independently OR¹ or NHR² wherein R¹ and R² are eachindependently a hydrogen atom or a C₁₋₂₂ alkyl group, or an optionallymodified amino acid residue, or X and Y in combination optionally form—O—;

Z is a hydrogen atom or a C₁₋₂₂ alkyl group; and

W is a C₁₋₂₂ alkyl group, a C₁₋₂₂ alkoxy group or a C₁₋₂₂ alkylaminogroup,

or a salt thereof.

(2) The cosmetic agent of the above-mentioned (1), wherein the cysteinederivative is one or more kinds selected fromN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid, andN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, and asalt thereof.

(3) The cosmetic agent of the above-mentioned (1), wherein the cysteinederivative is one or more kinds selected from a trans form ofN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid, and a trans form ofN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, and asalt thereof.

(4) A cosmetic agent comprising a cysteine derivative represented byformula (IX):

wherein

X′ is OR¹ or NHR² wherein R¹ and R² are each independently a hydrogenatom or a C₁₋₂₂ alkyl group, or an optionally modified amino acidresidue;

D is

(1) an aromatic heterocyclic group optionally substituted bysubstituent(s) selected from

-   -   (i) a hydroxyl group, and    -   (ii) a C₁₋₆ alkyl group optionally substituted by hydroxyl        group(s), or

(2) a C₁₋₂₂ alkyl group optionally substituted by hydroxyl group(s);

Z′ is a hydrogen atom or a C₁₋₂₂ alkyl group; and

W′ is a C₁₋₂₂ alkyl group, a C₁₋₂₂ alkoxy group or a C₁₋₂₂ alkylaminogroup,

or a salt thereof.

(5) A whitening agent comprising a cysteine derivative represented byformula (I):

wherein

X and Y are each independently OR¹ or NHR² wherein R¹ and R² are eachindependently a hydrogen atom or a C₁₋₂₂ alkyl group, or an optionallymodified amino acid residue, or X and Y in combination optionally form—O—;

Z is a hydrogen atom or a C₁₋₂₂ alkyl group; and

W is a C₁₋₂₂ alkyl group, a C₁₋₂₂ alkoxy group or a C₁₋₂₂ alkylaminogroup,

or a salt thereof.

(5a) The whitening agent of the above-mentioned (5), wherein thecysteine derivative is one or more kinds selected fromN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid, andN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, and asalt thereof.

(5b) The whitening agent of the above-mentioned (5), wherein thecysteine derivative is one or more kinds selected from a trans form ofN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid, and a trans form ofN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, and asalt thereof.

(5c) A whitening agent comprising a cysteine derivative represented byformula (IX):

wherein

X′ is OR¹ or NHR² wherein R¹ and R² are each independently a hydrogenatom or a C₁₋₂₂ alkyl group, or an optionally modified amino acidresidue;

D is

(1) an aromatic heterocyclic group optionally substituted bysubstituent(s) selected from

-   -   (i) a hydroxyl group, and    -   (ii) a C₁₋₆ alkyl group optionally substituted by hydroxyl        group(s), or

(2) a C₁₋₂₂ alkyl group optionally substituted by hydroxyl group(s);

Z′ is a hydrogen atom or a C₁₋₂₂ alkyl group; and

W′ is a C₁₋₂₂ alkyl group, a C₁₋₂₂ alkoxy group or a C₁₋₂₂ alkylaminogroup,

or a salt thereof.

(6) A cysteine derivative represented by formula (I):

wherein

X and Y are each independently OR¹ or NHR² wherein R¹ and R² are eachindependently a hydrogen atom or a C₁₋₂₂ alkyl group, or an optionallymodified amino acid residue, or X and Y in combination optionally form—O—;

Z is a hydrogen atom or a C₁₋₂₂ alkyl group; and

W is a C₁₋₂₂ alkyl group, a C₁₋₂₂ alkoxy group or a C₁₋₂₂ alkylaminogroup,

provided that N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid, andN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid anhydride areexcluded,

or a salt thereof.

(6a) The cysteine derivative or salt of the above-mentioned (6), whichis a trans form.

(7) A cysteine derivative represented by formula (IX):

wherein

X′ is OR¹ or NHR² wherein R¹ and R² are each independently a hydrogenatom or a C₁₋₂₂ alkyl group, or an optionally modified amino acidresidue;

D is

(1) an aromatic heterocyclic group optionally substituted bysubstituent(s) selected from

-   -   (i) a hydroxyl group, and    -   (ii) a C₁₋₆ alkyl group optionally substituted by hydroxyl        group(s), or

(2) a C₁₋₂₂ alkyl group optionally substituted by hydroxyl group(s);

Z′ is a hydrogen atom or a C₁₋₂₂ alkyl group; and

W′ is a C₁₋₂₂ alkyl group, a C₁₋₂₂ alkoxy group or a C₁₋₂₂ alkylaminogroup,

or a salt thereof.

(7a) The cysteine derivative or salt of the above-mentioned (7), whichis a trans form.

(8) Trans N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid, or a saltthereof.

(9) Trans N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethylester, or a salt thereof.

(10) Trans N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethylester, or a salt thereof, of the above-mentioned (9), which is a crystalform.

(11) Trans N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethylester, or a salt thereof, of the above-mentioned (10), which has meltingpoint of 138° C. to 141° C.

(12) A method of producing a cysteine derivative represented by formula(I):

wherein

X and Y are each independently OR′ or NHR² wherein R¹ and R² are eachindependently a hydrogen atom or a C₁₋₂₂ alkyl group, or an optionallymodified amino acid residue, or X and Y in combination optionally form—O—;

Z is a hydrogen atom or a C₁₋₂₂ alkyl group; and

W is a C₁₋₂₂ alkyl group, a C₁₋₂₂ alkoxy group or a C₁₋₂₂ alkylaminogroup,

provided that N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid, andN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid anhydride areexcluded,

which comprises reacting a compound represented by formula (IV):

wherein each symbol is as defined above,with a compound represented by formula (V):

wherein

A is a halogen atom; and

W is as defined above, or

a compound represented by formula (V′):

wherein W is as defined above.

(13) A method of selectively producing a trans form of a cysteinederivative represented by formula (I′):

wherein

Y″ is a C₁₋₂₂ alkoxy group;

Z″ is a C₁₋₂₂ alkyl group; and

W is a C₁₋₂₂ alkyl group, a C₁₋₂₂ alkoxy group or a C₁₋₂₂ alkylaminogroup,

or a salt thereof,

which comprises reacting a compound represented by formula (IV′):

wherein each symbol is as defined above,with a compound represented by formula (V):

wherein

A is a halogen atom; and

W is as defined above,

in the presence of an organic base, or

with a compound represented by formula (V′):

wherein W is as defined above,in the absence of a base.

The present invention provides cysteine derivatives having superiorstability, less odor and an eumelanin production suppressive effect,which enables provision of a whitening agent, cosmetic agent or skinexternal preparation, which contains the derivative as an activeingredient and is superior in the long-term preservation stability.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the present invention and many of theattendant advantages thereof will be readily obtained as the same becomebetter understood by reference to the following detailed descriptionwhen considered in connection with the accompanying drawings, wherein:

FIG. 1 shows the results of a time-course stability test of2-methylthiazolidine-2,4-dicarboxylic acid (CP),N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid (N-Ac-CP),2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (CP2Et) andN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester(N-Ac-CP2Et) at pH 4, 70° C.

FIG. 2 shows the results of a time-course stability test of CP, N-Ac-CP,CP2Et and N-Ac-CP2Et at pH 5, 70° C.

FIG. 3 shows the results of a time-course stability test of CP, N-Ac-CPand N-Ac-CP2Et at pH 6, 70° C.

FIG. 4 shows the results of a time-course stability test of CP, N-Ac-CPand N-Ac-CP2Et at pH 7, 70° C.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The terms to be used in the present specification are defined in thefollowing.

The term “C₁₋₂₂ alkyl group” means a straight chain or branched chainhydrocarbon group having 1 to 22 carbon atoms, and examples thereofinclude a methyl group, an ethyl group, an isopropyl group, a propylgroup, a butyl group, an isobutyl group, a sec-butyl group, a tert-butylgroup, a pentyl group, a sec-pentyl group, a tert-pentyl group, anisopentyl group, a hexyl group, a heptyl group, an octyl group, a2-ethylhexyl group, a tert-octyl group, a nonyl group, an isononylgroup, a decyl group, an isodecyl group, an undecyl group, a dodecylgroup, a tridecyl group, an isotridecyl group, a tetradecyl group, apentadecyl group, a hexadecyl group, an isohexadecyl group, a heptadecylgroup, an octadecyl group, an isooctadecyl group, an oleyl group, abehenyl group, and the like.

Examples of the “C₁₋₁₆ alkyl group” include a methyl group, an ethylgroup, an isopropyl group, a propyl group, a butyl group, an isobutylgroup, a sec-butyl group, a tert-butyl group, a pentyl group, asec-pentyl group, a tert-pentyl group, an isopentyl group, a hexylgroup, a heptyl group, an octyl group, a 2-ethylhexyl group, atert-octyl group, a nonyl group, an isononyl group, a decyl group, anisodecyl group, an undecyl group, a dodecyl group, a tridecyl group, anisotridecyl group, a tetradecyl group, a pentadecyl group, a hexadecylgroup, an isohexadecyl group, and the like.

Examples of the “C₁₋₆ alkyl group” include a methyl group, an ethylgroup, an isopropyl group, a propyl group, a butyl group, an isobutylgroup, a sec-butyl group, a tert-butyl group, a pentyl group, asec-pentyl group, a tert-pentyl group, an isopentyl group, a hexylgroup, and the like.

The term “C₁₋₂₂ alkoxy group” means a hydroxyl group substituted by theabove-mentioned “C₁₋₂₂ alkyl group”, and examples thereof include amethoxy group, an ethoxy group, a propoxy group, an isopropyloxy group,a butoxy group, an isobutyloxy group, a tert-butyloxy group, a pentyloxygroup, a hexyloxy group, a heptyloxy group, an octyloxy group, anonyloxy group, a decyloxy group, an undecyloxy group, a dodecyloxygroup, a tridecyloxy group, a tetradecyloxy group, a pentadecyloxygroup, a hexadecyloxy group, a heptadecyloxy group, an octadecyloxygroup, a nonadecyloxy group, an eicosyloxy group, a heneicosyloxy group,a docosyloxy group, and the like.

Examples of the “C₁₋₆ alkoxy group” include a methoxy group, an ethoxygroup, a propoxy group, an isopropyloxy group, a butoxy group, anisobutyloxy group, a tert-butyloxy group, a pentyloxy group, a hexyloxygroup, and the like.

The term “C₁₋₂₂ alkylamino group” means an amino group substituted bythe above-mentioned “C₁₋₂₂ alkyl group(s)”, and examples thereof includea methylamino group, an ethylamino group, a propylamino group, anisopropylamino group, a butylamino group, an isobutylamino group, atert-butylamino group, a pentylamino group, a hexylamino group, aheptylamino group, an octylamino group, a nonylamino group, a decylaminogroup, an undecylamino group, a dodecylamino group, a tridecylaminogroup, a tetradecylamino group, a pentadecylamino group, ahexadecylamino group, a heptadecylamino group, an octadecylamino group,a nonadecylamino group, an eicosylamino group, a heneicosylamino group,a docosylamino group, and the like.

Examples of the “C₁₋₆ alkylamino group” include a methylamino group, anethylamino group, a propylamino group, an isopropylamino group, abutylamino group, an isobutylamino group, a tert-butylamino group, apentylamino group, and a hexylamino group.

Examples of “halogen atom” include a chlorine atom, a bromine atom, afluorine atom, and an iodine atom.

Each substituent in the above-mentioned formula (I) is explained in thefollowing.

X and Y are each independently OR¹ or NHR² wherein R¹ and R² are eachindependently a hydrogen atom or a C₁₋₂₂ alkyl group, or an optionallymodified amino acid residue, or X and Y in combination optionally form—O—.

The “C₁₋₂₂ alkyl group” for R¹ or R² is preferably a C₁₋₆ alkyl group,more preferably a methyl group, an ethyl group, or an isopropyl group,still more preferably an ethyl group.

The “optionally modified amino acid residue” for X or Y means a groupobtained by removal of one hydrogen atom from the amino group of the“optionally modified amino acid”. Examples of the “amino acid” of the“optionally modified amino acid” include α-amino acids, β-amino acids,γ-amino acids, and the like, and α-amino acids are preferable. Cyclicamino acids such as proline and the like are encompassed in the “aminoacid”. When the “amino acid” is L-form or D-form, all isomers and amixture thereof are also encompassed in the above-mentioned “aminoacid”. The “amino acid” is preferably glycine, alanine, valine, or thelike, more preferably glycine or alanine, still more preferably glycine.

The above-mentioned “amino acid” is optionally modified at any position.The “modified amino acid residue” is preferably a carboxylgroup-modified amino acid residue, more preferably an amino acid residuewherein the carboxyl group is esterified by a C₁₋₂₂ alkoxy group(preferably a methoxy group, an ethoxy group) or amidated by a C₁₋₂₂alkylamino group.

The “optionally modified amino acid residue” is preferably a groupderived from glycine ethyl ester, glycine methyl ester, or alaninemethyl ester.

X is preferably OR¹ wherein R¹ is as defined above, or an optionallymodified amino acid residue;

more preferably OR¹ wherein R¹ is as defined above, or an α-amino acidresidue wherein the carboxyl group is esterified by a C₁₋₂₂ alkoxy groupor amidated by a C₁₋₂₂ alkylamino group; further more preferably OR¹wherein R¹ is as defined above, or an α-amino acid residue wherein thecarboxyl group is esterified by a C₁₋₂₂ alkoxy group (preferably amethoxy group, an ethoxy group);

still more preferably OR¹′ wherein R¹′ is a hydrogen atom or a C₁₋₆alkyl group (preferably a methyl group, an ethyl group, an isopropylgroup), or an α-amino acid residue (preferably glycine, alanine) whereinthe carboxyl group is esterified by a C₁₋₆ alkoxy group (preferably amethoxy group, an ethoxy group);

particularly preferably a hydroxyl group, a methoxy group, an ethoxygroup, an isopropoxy group, or a group derived from glycine methylester, glycine ethyl ester or alanine methyl ester, particularly ahydroxyl group or a methoxy group.

Y is preferably OR¹ wherein R¹ is as defined above, more preferably OR¹′wherein R¹′ is as defined above, further more preferably a hydroxylgroup, a methoxy group or an ethoxy group, still more preferably ahydroxyl group or a methoxy group.

Alternatively, preferably, X and Y in combination optionally form —O—.

Z is a hydrogen atom or a C₁₋₂₂ alkyl group.

The “C₁₋₂₂ alkyl group” for Z is preferably a C₁₋₆ alkyl group, morepreferably a methyl group.

Z is preferably a hydrogen atom or a C₁₋₆ alkyl group, more preferably ahydrogen atom or a methyl group.

W is a C₁₋₂₂ alkyl group, a C₁₋₂₂ alkoxy group or a C₁₋₂₂ alkylaminogroup.

The “C₁₋₂₂ alkyl group” for W is preferably a C₁₋₁₆ alkyl group, morepreferably a methyl group, a nonyl group or a pentadecyl group, stillmore preferably a methyl group.

The “C₁₋₂₂ alkoxy group” for W is preferably a C₁₋₆ alkoxy group, morepreferably a tert-butoxy group.

The “C₁₋₂₂ alkylamino group” for W is preferably a C₁₋₆ alkylaminogroup.

W is preferably a C₁₋₂₂ alkyl group or a C₁₋₂₂ alkoxy group, morepreferably a C₁₋₁₆ alkyl group or a C₁₋₆ alkoxy group, still morepreferably a methyl group, a nonyl group, a pentadecyl group or atert-butoxy group, particularly preferably a methyl group or atert-butoxy group.

The cysteine derivative represented by the formula (I) is preferably acysteine derivative wherein

-   X is OR¹ wherein R¹ is as defined above, or an optionally modified    amino acid residue,-   Y is OR¹ wherein R¹ is as defined above, or-   X and Y in combination optionally form —O—,-   Z is a hydrogen atom or a C₁₋₂₂ alkyl group, and-   W is a C₁₋₂₂ alkyl group or a C₁₋₂₂ alkoxy group,

more preferably a cysteine derivative wherein

-   X is OR¹ wherein R¹ is as defined above, or an α-amino acid residue    wherein the carboxyl group is esterified by a C₁₋₂₂ alkoxy group or    amidated by a C₁₋₂₂ alkylamino group,-   Y is OR¹ wherein R¹ is as defined above, or-   X and Y in combination optionally form —O—,-   Z is a hydrogen atom or a C₁₋₂₂ alkyl group, and-   W is a C₁₋₂₂ alkyl group or a C₁₋₂₂ alkoxy group,

further more preferably a cysteine derivative wherein X is OR¹ whereinR¹ is as defined above, or an α-amino acid residue wherein the carboxylgroup is esterified by a C₁₋₂₂ alkoxy group,

-   Y is OR¹ wherein R¹ is as defined above, or-   X and Y in combination optionally form —O—,-   Z is a hydrogen atom or a C₁₋₂₂ alkyl group, and-   W is a C₁₋₂₂ alkyl group or a C₁₋₂₂ alkoxy group,

still more preferably a cysteine derivative wherein X is OR¹′ whereinR¹′ is a hydrogen atom or a C₁₋₆ alkyl group, or a α-amino acid residue(preferably glycine, alanine) wherein the carboxyl group is esterifiedby a C₁₋₆ alkoxy group (preferably a methoxy group, an ethoxy group),

-   Y is OR¹′ wherein R¹′ is a hydrogen atom or a C₁₋₆ alkyl group, or-   X and Y in combination optionally form —O—,-   Z is a hydrogen atom or a C₁₋₆ alkyl group, and-   W is a C₁₋₁₆ alkyl group or a C₁₋₆ alkoxy group,

particularly preferably a cysteine derivative wherein X is a hydroxylgroup, a methoxy group, an ethoxy group, an isopropoxy group, or a groupderived from glycine methyl ester, glycine ethyl ester or alanine methylester,

-   Y is a hydroxyl group, a methoxy group or an ethoxy group, or-   X and Y in combination optionally form —O—,-   Z is a hydrogen atom or a methyl group, and-   W is a methyl group, a nonyl group, a pentadecyl group or a    tert-butoxy group.

Specifically, N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid, andN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester arepreferable, and N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester is more preferable.

The above-mentioned cysteine derivative represented by formula (I)(N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid andN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid anhydride areexcluded) is a novel compound.

Each substituent in the above-mentioned formula (IX) is explained in thefollowing.

X′ is OR¹ or NHR² wherein R¹ and R² are each independently a hydrogenatom or a C₁₋₂₂ alkyl group, or an optionally modified amino acidresidue.

Examples of the “OR¹”, “NHR²”, and “optionally modified amino acidresidue” for X′ include those similar to the aforementioned “OR¹”,“NHR²”, and “optionally modified amino acid residue” for X or Y.

X′ is preferably OR′ wherein R¹ is as defined above, more preferablyOR¹′ wherein R¹′ is a hydrogen atom or a C₁₋₆ alkyl group (preferably amethyl group), still more preferably a hydroxyl group or a methoxygroup.

D is

-   (1) an aromatic heterocyclic group optionally substituted by    substituent(s) selected from    -   (i) a hydroxyl group, and    -   (ii) a C₁₋₆ alkyl group optionally substituted by hydroxyl        group(s), or-   (2) a C₁₋₂₂ alkyl group optionally substituted by hydroxyl group(s).

Examples of the “aromatic heterocyclic group” of the “aromaticheterocyclic group optionally substituted by substituent(s) selectedfrom (i) a hydroxyl group, and (ii) a C₁₋₆ alkyl group optionallysubstituted by hydroxyl group(s)” for D include a 4- to 7-membered(preferably a 5- or 6-membered) monocyclic aromatic heterocyclic groupcontaining, as a ring-constituting atom besides carbon atoms, 1 to 4hetero atoms selected from an oxygen atom, a sulfur atom (the sulfuratom is optionally oxidized) and a nitrogen atom, and fused aromaticheterocyclic group. Examples of the fused aromatic heterocyclic groupinclude a group derived from a fused ring wherein a ring correspondingto the 4- to 7-membered monocyclic aromatic heterocyclic group and 1 or2 rings selected from a 5- or 6-membered aromatic heterocycle containing1 or 2 nitrogen atoms (e.g., pyrrole, imidazole, pyrazole, pyrazine,pyridine, pyrimidine), a 5-membered aromatic heterocycle containing onesulfur atom (e.g., thiophene) and a benzene ring are condensed, and thelike.

Preferable examples of the aromatic heterocyclic group include

monocyclic aromatic heterocyclic groups such as furyl (e.g., 2-furyl,3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyridyl (e.g.,2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl,4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), pyrrolyl (e.g.,2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl,4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl),thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl(e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), oxazolyl (e.g.,2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 1,2,5-oxadiazol-3-yl,1,3,4-oxadiazol-2-yl), thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl,1,3,4-thiadiazol-2-yl), triazolyl (e.g., 1,2,4-triazol-1-yl,1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl,1,2,3-triazol-4-yl), tetrazolyl (e.g., tetrazol-1-yl, tetrazol-5-yl),triazinyl (e.g., 1,2,4-triazin-3-yl, 1,2,4-triazin-5-yl,1,2,4-triazin-6-yl), and the like;

fused aromatic heterocyclic groups such as quinolyl (e.g., 2-quinolyl,3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolyl (e.g., 3-isoquinolyl),quinazolyl (e.g., 2-quinazolyl, 4-quinazolyl), quinoxalyl (e.g.,2-quinoxalyl, 6-quinoxalyl), benzofuranyl (e.g., 2-benzofuranyl,3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl,7-benzofuranyl), benzothienyl (e.g., 2-benzothienyl, 3-benzothienyl),benzoxazolyl (e.g., 2-benzoxazolyl), benzisoxazolyl (e.g.,7-benzisoxazolyl), benzothiazolyl (e.g., 2-benzothiazolyl,6-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-1-yl,benzimidazol-2-yl, benzimidazol-5-yl), benzotriazolyl (e.g.,1H-1,2,3-benzotriazol-1-yl, 1H-1,2,3-benzotriazol-5-yl), indolyl (e.g.,indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), indazolyl (e.g.,2H-indazol-3-yl), pyrrolopyrazinyl (e.g., 1H-pyrrolo[2,3-b]pyrazin-2-yl,1H-pyrrolo[2,3-b]pyrazin-6-yl), imidazopyridinyl (e.g.,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,2H-imidazo[1,2-a]pyridin-3-yl), imidazopyrazinyl (e.g.,1H-imidazo[4,5-b]pyrazin-2-yl), pyrazolopyridinyl (e.g.,1H-pyrazolo[4,3-c]pyridin-3-yl), thienopyrazolyl (e.g.,1H-thieno[2,3-c]pyrazol-5-yl), pyrazolotriazinyl (e.g.,pyrazolo[5,1-c][1,2,4]triazin-3-yl), triazolopyrimidinyl (e.g.,[1,2,4]triazolo[1,5-a]pyrimidin-2-yl), phthalazinyl, and the like; andthe like. The aromatic heterocyclic group is preferably a monocyclicaromatic heterocyclic group, more preferably pyridyl (preferably4-pyridyl).

The “aromatic heterocyclic group” optionally has substituent(s) selectedfrom

-   (i) a hydroxyl group, and-   (ii) a C₁₋₆ alkyl group (preferably a methyl group) optionally    substituted by hydroxyl group(s), at any substitutable position.    While the number of the substituents is not particularly limited, it    is preferably 1 to 6, more preferably 1 to 4, still more preferably    1 to 3. When the number of the substituents is 2 or more, the    respective substituents may be the same or different.

The “aromatic heterocyclic group optionally substituted bysubstituent(s) selected from (i) a hydroxyl group, and (ii) a C₁₋₆ alkylgroup optionally substituted by hydroxyl group(s)” for D is preferablyan aromatic heterocyclic group optionally substituted by 1 to 6substituents selected from (i) a hydroxyl group, and (ii) a C₁₋₆ alkylgroup optionally substituted by hydroxyl group(s),

more preferably a monocyclic aromatic heterocyclic group [preferablypyridyl (preferably 4-pyridyl)] optionally substituted by 1 to 4substituents selected from (i) a hydroxyl group, and (ii) a C₁₋₆ alkylgroup optionally substituted by hydroxyl group(s),

still more preferably a monocyclic aromatic heterocyclic group[preferably pyridyl (preferably 4-pyridyl)] optionally substituted by 1to 4 (preferably 1 to 3) substituents selected from a hydroxyl group, amethyl group and a hydroxymethyl group,

particularly preferably3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl.

The “C₁₋₂₂ alkyl group” of the “C₁₋₂₂ alkyl group optionally substitutedby hydroxyl group(s)” for D is preferably a C₁₋₁₆ alkyl group, morepreferably a C₁₋₆ alkyl group, particularly preferably a pentyl group.

The “C₁₋₂₂ alkyl group” optionally has hydroxyl group(s) at anysubstitutable position. While the number of the hydroxyl groups is notparticularly limited, it is preferably 1 to 16, more preferably 1 to 10,still more preferably 1 to 6, particularly preferably 1 to 5.

The “C₁₋₂₂ alkyl group” of the “C₁₋₂₂ alkyl group optionally substitutedby hydroxyl group(s)” for D is preferably a C₁₋₂₂ alkyl group optionallysubstituted by 1 to 16 hydroxyl groups, more preferably a C₁₋₁₆ alkylgroup optionally substituted by 1 to 10 hydroxyl groups,

still more preferably a C₁₋₆ alkyl group (preferably pentyl group)optionally substituted by 1 to 6 (preferably 1 to 5) hydroxyl groups,

particularly preferably 1,2,3,4,5-pentahydroxypentyl.

D is preferably

-   (1) an aromatic heterocyclic group optionally substituted by 1 to 6    substituents selected from    -   (i) a hydroxyl group, and    -   (ii) a C₁₋₆ alkyl group optionally substituted by hydroxyl        group(s), or-   (2) a C₁₋₂₂ alkyl group optionally substituted by 1 to 16 hydroxyl    groups,    -   more preferably-   (1) a monocyclic aromatic heterocyclic group [preferably pyridyl    (preferably 4-pyridyl)] optionally substituted by 1 to 4    substituents selected from    -   (i) a hydroxyl group, and    -   (ii) a C₁₋₆ alkyl group optionally substituted by hydroxyl        group(s), or-   (2) a C₁₋₁₆ alkyl group, optionally substituted by 1 to 10 hydroxyl    groups    -   still more preferably-   (1) a monocyclic aromatic heterocyclic group [preferably pyridyl    (preferably 4-pyridyl)] optionally substituted by 1 to 4 (preferably    1 to 3) substituents selected from a hydroxyl group, a methyl group    and a hydroxymethyl group, or-   (2) a C₁₋₆ alkyl group (preferably pentyl group) optionally    substituted by 1 to 6 (preferably 1 to 5) hydroxyl groups,    -   particularly preferably-   (1) 3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl, or-   (2) 1,2,3,4,5-pentahydroxypentyl.

Z′ is a hydrogen atom or a C₁₋₂₂ alkyl group.

Z′ is preferably a hydrogen atom.

W′ is a C₁₋₂₂ alkyl group, a C₁₋₂₂ alkoxy group or a alkylamino group.

W′ is preferably a C₁₋₂₂ alkyl group, more preferably a C₁₋₁₆ alkylgroup, still more preferably a C₁₋₆ alkyl group, particularly preferablya methyl group.

The cysteine derivative represented by formula (IX) is preferably acysteine derivative wherein

-   X′ is OR¹ wherein R¹ is as defined above,-   D is-   (1) an aromatic heterocyclic group optionally substituted by 1 to 6    substituents selected from    -   (i) a hydroxyl group, and    -   (ii) a C₁₋₆ alkyl group optionally substituted by hydroxyl        group(s), or-   (2) a C₁₋₂₂ alkyl group optionally substituted by 1 to 16 hydroxyl    groups,-   Z′ is a hydrogen atom, and-   W′ is a C₁₋₂₂ alkyl group,

more preferably a cysteine derivative wherein X′ is OR¹′ wherein R¹′ isa hydrogen atom or a C₁₋₆ alkyl group (preferably a methyl group),

-   D is-   (1) a monocyclic aromatic heterocyclic group [preferably pyridyl    (preferably 4-pyridyl)] optionally substituted by 1 to 4    substituents selected from    -   (i) a hydroxyl group, and    -   (ii) a C₁₋₆ alkyl group optionally substituted by hydroxyl        group(s), or-   (2) a C₁₋₁₆ alkyl group optionally substituted by 1 to 10 hydroxyl    groups,-   Z′ is a hydrogen atom, and-   W′ is a C₁₋₁₆ alkyl group,

still more preferably a cysteine derivative wherein X′ is OR¹′ whereinR¹′ is a hydrogen atom or a C₁₋₆ alkyl group (preferably a methylgroup),

-   D is-   (1) a monocyclic aromatic heterocyclic group [preferably pyridyl    (preferably 4-pyridyl)] optionally substituted by 1 to 4 (preferably    1 to 3) substituents selected from a hydroxyl group, a methyl group    and a hydroxymethyl group, or-   (2) a C₁₋₆ alkyl group (preferably pentyl group) optionally    substituted by 1 to 6 (preferably 1 to 5) hydroxyl groups,-   Z′ is a hydrogen atom, and-   W′ is a C₁₋₆ alkyl group (preferably a methyl group),

particularly preferably a cysteine derivative wherein X′ is a hydroxylgroup or a methoxy group,

-   D is-   (1) 3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl, or-   (2) 1,2,3,4,5-pentahydroxypentyl,-   Z′ is a hydrogen atom, and-   W′ is a methyl group.

Specifically,N-acetyl-2-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]thiazolidine-4-carboxylicacid, N-acetyl-2-(1,2,3,4,5-pentahydroxypentyl)thiazolidine-4-carboxylicacid methyl ester andN-acetyl-2-(1,2,3,4,5-pentahydroxypentyl)thiazolidine-4-carboxylic acidare preferable.

The cysteine derivative represented by formula (I) or a salt thereof,and the cysteine derivative represented by formula (IX) or a saltthereof are collectively referred to as “the cysteine derivative of thepresent invention”.

While the cysteine derivative of the present invention contains(2R,4R)-form, (2S,4S)-form, (2R,4S)-form and (2S,4R)-form based on theasymmetric carbon atoms at the 2-position and 4-position of thethiazolidine ring, all such isomers and mixtures thereof are encompassedin the cysteine derivative of the present invention (excluding compoundwherein D and Z′ are the same). In the present specification,(2R,4R)-form, (2S,4S)-form and a mixture thereof are referred to as thecis form, and (2R,4S)-form, (2S,4R)-form and a mixture thereof aresometimes referred to as the trans form.

The cysteine derivative of the present invention is preferably a transform from the aspect of stability. Particularly, the trans form of thecysteine derivative of the present invention is superior in thepreservation stability under acidic conditions (e.g., pH 5 or below(preferably pH 4 or below)), and therefore, is highly useful when addedto cosmetic agents such as a whitening agent and the like having such apH.

Particularly, the cysteine derivative of the present invention ispreferably a trans form ofN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid or a salt thereof(i.e., (2S,4R)—N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid,(2R,4S)—N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid, or amixture thereof, or a salt thereof); a trans form ofN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester or asalt thereof (i.e.,(2S,4R)—N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethylester, (2R,4S)—N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester, or a mixture thereof, or a salt thereof), more preferablya trans form of N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester or a salt thereof.

Examples of the salt of the cysteine derivative include salts with aninorganic base, salts with an organic base, salts with an amino acid,and the like.

Examples of the salt with an inorganic base include a sodium salt,potassium salt, calcium salt, magnesium salt, ammonium salt, and thelike.

Examples of the salt with an organic base include salts withmethylamine, diethylamine, trimethylamine, triethylamine, ethanolamine,diethanolamine, triethanolamine, ethylenediamine,tris(hydroxymethyl)methylamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, guanidine, pyridine, picoline, choline,cinchonine, meglumine, and the like.

Examples of the salt with an amino acid include salts with lysine,arginine, and histidine.

Each salt can be obtained by reacting the cysteine derivative of thepresent invention with an inorganic base, an organic base. or an aminoacid according to a method known per se.

The cysteine derivative of the present invention can be used as acysteine prodrug. In the present specification, the term “cysteineprodrug” refers to a compound having improved stability and the like bymodifying cysteine, which is enzymatically or non-enzymaticallydecomposed, and converted to cysteine or a compound having a sulfanylgroup which shows physiological activity in the living body. Therefore,the cysteine derivative of the present invention can be used as asubstitute for cysteine as long as it is effectively converted tocysteine or a compound having a sulfanyl group in the system.

In one embodiment of the present invention, the cysteine derivative ofthe present invention can be used as an eumelanin production suppressingagent, a whitening agent, or a pigmented spot-preventing or treatingagent. These applications utilize properties of the cysteine derivativeof the present invention, where it maintains a stable dosage form but isdecomposed into cysteine comparatively rapidly due to an enzyme such asacylase and the like at an action site via skin absorption.

In another embodiment of the present invention, the cysteine derivativeof the present invention can be added to various cosmetic agents or skinexternal preparations. The cosmetic agent and the skin externalpreparation of the present invention may take any form and are free ofany particular limitation. They can be in any form such as solution,paste, gel, solid, powder and the like. Specific examples thereofinclude skin lotion, toner, cream, skin milk, serum, shampoo, hairrinse, conditioner, enamel, foundation, eyeliner, eyebrow pencil,mascara, chapstick, face powder, powder, facial mask, perfume, cologne,cleansing foam, cleansing oil, cleansing gel, dentifrice, soap, aerosol,bath agent, hair-growth promoter, and sun protectant.

When the cysteine derivative of the present invention is added to acosmetic agent or skin external preparation, the lower limit value ofaddition is not particularly limited as long as its effect can beexhibited. It is preferably 0.0001 wt %, based on the total weight ofthe cosmetic agent or skin external preparation. For a sufficient effectto be exhibited, it is more preferably 0.001 wt %, further morepreferably 0.01 wt %, still more preferably 0.1 wt %, especiallypreferably 0.5 wt %, particularly preferably 1 wt %, based on the totalweight of the cosmetic agent or skin external preparation.

When the cysteine derivative of the present invention is added to acosmetic agent or skin external preparation, the upper limit value ofaddition is not particularly limited as long as its effect can beexhibited. It is preferably 20 wt %, based on the total weight of thecosmetic agent or skin external preparation. It is more preferably 18 wt%, further more preferably 16 wt %, still more preferably 14 wt %,especially preferably 12 wt %, and particularly preferably 10 wt %,based on the total weight of the cosmetic agent or skin externalpreparation.

When a cosmetic composition or whitening composition of the presentinvention is to be provided, various components (for example acosmetically acceptable carrier), generally usable for cosmeticcomposition, skin external preparations and quasi-drugs may be added, inaddition to the cysteine derivative of the present invention, within therange not inhibiting the effect of the invention.

The cosmetically acceptable carrier include for example, oily component,surfactant, amino acids, amino acid derivatives, lower alcohol,polyhydric alcohol, sugar alcohol and alkylene oxide adduct thereof,water-soluble polymer, antimicrobial agent and disinfectant,anti-inflammatory agent, analgesic, antifungal agent, stratum corneumsoftening and peeling agent, skin colorant, hormone, UV absorber,hair-growth promoter, whitening agent, antiperspirant and astringentactive ingredient, perspiration deodorant, vitamin, vasodilator, crudedrug, pH adjuster, viscosity modifier, pearly pigment, natural perfume,synthetic perfume, dye, antioxidant, preservative, emulsifier, fat andwax, silicone compound, balm, and the like.

Examples of the oily component include saturated or unsaturated fattyacid and higher alcohols obtained therefrom, straight chain or branchedchain fatty alcohol esters such as myristyl myristate, myristylpalmitate, myristyl stearate, myristyl isostearate, myristyl oleate,myristyl behenate, myristyl erucate, cetyl myristate, cetyl palmitate,cetyl stearate, cetyl isostearate, cetyl oleate, cetyl behenate, cetylerucate, stearyl myristate, stearyl palmitate, stearyl stearate, stearylisostearate, stearyl oleate, stearyl behenate, stearyl erucate,isostearyl myristate, isostearyl palmitate, isostearyl stearate,isostearyl isostearate, isostearyl oleate, isostearyl behenate,isostearyl erucate, behenyl myristate, behenyl palmitate, behenylstearate, behenyl isostearate, behenyl oleate, behenyl behenate, behenylerucate, erucyl myristate, erucyl palmitate, erucyl stearate, erucylisostearate, erucyl oleate, erucyl behenate, erucyl erucate and thelike, squalane, squalene, castor oil and/or hydrogenated castor oil anda derivative thereof, glycerides such as hydroxystearic acidmonoglyceride, hydroxystearic acid diglyceride, isostearic acidmonoglyceride, isostearic acid diglyceride, oleic acid monoglyceride,oleic acid diglyceride, ricinoleic acid monoglyceride, ricinoleic aciddiglyceride, linoleic acid monoglyceride, linoleic acid diglyceride,linolenic acid monoglyceride, linolenic acid diglyceride, tartaric acidmonoglyceride, tartaric acid diglyceride, citric acid monoglyceride,citric acid diglyceride, malic acid monoglyceride, malic aciddiglyceride and ethylene oxide 1-30 mol adduct of these glycerides, andthe like, beeswax, lanolins including liquid and purified lanolin and aderivative thereof, oily starting materials derived from animals andplants such as almond oil, avocado oil, olive oil, rape seed oil,coconut oil, macadamia nut oil, jojoba oil, carnauba wax, sesame oil,cacao oil, palm oil, mink oil, Japan wax, candelilla wax, whale wax andthe like, oily starting materials derived from petroleum and mineralsuch as paraffin, microcrystalline wax, liquid paraffin, petrolatum,ceresin and the like, silicons such as silicone polymers includingmethylpolysiloxane, polyoxyethylene.methylpolysiloxane,polyoxypropylene.methylpolyoxysiloxane, poly(oxyethylene,oxypropylene).methylpolysiloxane, methylphenylpolysiloxane, fatty acidmodified polysiloxane, aliphatic alcohol modified polysiloxane, aminoacid modified polysiloxane and the like, and the like, resin acid, fattyacid ester, ketones, and the like.

Examples of the surfactant include anion surfactants, for example,N-long chain acylamino acid salts such as N-long chain acyl acidic aminoacid salts (e.g., N-long chain acylglutamic acid salt, N-long chainacylaspartic acid salt and the like), N-long chain acyl neutral aminoacid salts (e.g., N-long chain acylglycine salt, N-long chainacylalanine salt, N-long chain acyltreonine salt and the like) and thelike, N-long chain fatty acid acyl-N-methyltaurine salt, alkylsulfateand alkylene oxide adduct thereof, fatty acid amide ether sulfate, metalsalt and weak basic salt of fatty acid, sulfosuccinic acid typesurfactant, alkylphosphate and alkylene oxide adduct thereof,alkylethercarboxylic acid and the like; non-ionic surfactants, such asether type surfactants (e.g., glycerolether and alkylene oxide adductthereof and the like), ester type surfactants (e.g., glycerol ester andalkylene oxide adduct thereof and the like), ether ester typesurfactants (e.g., sorbitan ester and alkylene oxide adduct thereof andthe like), ester type surfactants (e.g., polyoxyalkylene fatty acidester, glycerol ester, fatty acid polyglycerol ester, acylamino acidpolyglycerol ester, sorbitan ester, sucrose fatty acid ester and thelike), alkyl glucosides, nitrogen-containing type non-ionic surfactants(e.g., hydrogenated castor oil pyroglutamic acid diester and ethyleneoxide adduct thereof, as well as fatty acid alkanolamide and the like),and the like; cation surfactants such as aliphatic amine salts (e.g.,alkylammonium chloride, dialkylammonium chloride and the like),quaternary ammonium salts thereof, aromatic quaternary ammonium salts(e.g., benzalkonium salt and the like), fatty acid acylarginine ester,alkyloxyhydroxypropylarginine salt and the like; and betaine typesurfactants such as alkylbetaine, alkylamidebetaine, aminopropionate,carboxybetaine and the like, ampholytic surfactants such asaminocarboxylic acid type surfactant, imidazoline type surfactant andthe like, and the like.

Examples of the amino acids include glycine, alanine, serine, threonine,arginine, glutamic acid, aspartic acid, leucine, valine, and the like.

Examples of the amino acid derivative include pyrrolidonecarboxylic acidand a salt thereof, trimethylglycine, lauroyllysine, and the like.

Examples of the lower alcohol include ethanol, propanol, isopropanol,butanol, and the like.

Examples of the polyhydric alcohol include glycerol, diglycerol,ethylene glycol, 1,3-butylene glycol, propylene glycol, isoprene glycol,and the like.

Examples of the sugar alcohol and an alkylene oxide adduct thereofinclude mannitol, erythritol, and the like.

Examples of the water-soluble polymer include polyamino acids includingpolyglutamic acid and polyaspartic acid, and a salt thereof,polyethylene glycol, gum arabics, alginates, xanthan gum, hyaluronicacid, hyaluronic acid salts, chitin, chitosan, aqueous chitin,carboxyvinyl polymer, carboxymethylcellulose, hydroxyethylcellulose,polyacrylamide, polyvinyl alcohol, polyvinylpyrrolidone,hydroxypropyltrimethylammonium chloride, polydimethylmethylenepiperidiumchloride, polyvinylpyrrolidone derivative quaternary ammonium,cationated protein, collagen decomposition product and a derivativethereof, acylated protein, polyglycerol, and the like.

Examples of the antimicrobial agent and disinfectant include4-hydroxybenzoic acid and a salt thereof and ester thereof, triclosan,chlorhexidine, phenoxyethanol, menthol, mint oil, glyceryl caprate,glyceryl caprylate, salicylic acid-N-alkylamide, and the like.

Examples of the anti-inflammatory agent, analgesic, antifungal agent,stratum corneum softening and peeling agent, skin colorant and hormoneinclude Japanese cypress thiol, hydrocortisone(V), ε-aminocarboxylicacid, azulene, allantoin, glycyrrhizic acid derivative, β-glycyrrhetinicacid, and the like.

The UV absorber is, for example, an organic substance (photoprotectivefilter) which is liquid or crystal at room temperature, and can absorbultraviolet rays and release the absorbed energy as radiation having alonger wavelength (for example, heat). Examples thereof include UV-Bfilter and UV-A filter. The UV-B filter can be oil-soluble orwater-soluble. Examples of the oil-soluble substance include3-benzylidenecamphor or 3-benzylidenenorcamphor and a derivative thereof(e.g., 3-(4-methylbenzylidene)-camphor); 4-aminobenzoic acid derivative(preferably 4-(dimethylamino)-benzoic acid-2-ethylhexyl ester,4-(dimethylamino)-benzoic acid-2-octyl ester, 4-(dimethylamino)-benzoicacid pentyl ester); cinnamic acid ester (preferably 4-methoxycinnamicacid-2-ethylhexyl ester, 4-methoxycinnamic acid propyl ester,4-methoxycinnamic acid isopentyl ester, 2-cyano-3,3-phenylcinnamicacid-2-ethylhexyl ester (Octocrylene)); salicylic acid ester (preferablysalicylic acid-2-ethylhexyl ester, salicylic acid-4-isopropylbenzylester, salicylic acid homomenthyl ester); benzophenone derivative(preferably 2-hydroxy-4-methoxybenzophenone,2-hydroxy-4-methoxy-4′-methylbenzophenone,2,2′-dihydroxy-4-methoxybenzophenone); benzalmalonic acid ester(preferably 4-methoxybenzalmalonic acid di-2-ethylhexyl ester); triazinederivative (e.g.,2,4,6-trianilino-(p-carbo-2′-ethyl-1′-hexyloxy)-1,3,5-triazine,octyl.triazone, dioctyl.butamide.triazone (Uvasorb (registered trademark) HEB)); propane-1,3-dione (e.g.,1-(4-t-butylphenyl)-3-(4′-methoxyphenyl)-propane-1,3-dione);ketotricyclo(5.2.1.0)decane derivative, and the like. Examples of thewater-soluble substance include 2-phenylbenzimidazole-5-sulfonic acidand alkali metal salt, alkaline earth metal salt, ammonium salt,alkylammonium salt, alkanolammonium salt and glucammonium salt thereof;sulfonic acid derivative of benzophenone (preferably2-hydroxy-4-methoxybenzophenone-5-sulfonic acid and a salt thereof);sulfonic acid derivative of 3-benzylidenecamphor (e.g.,4-(2-oxo-3-bornylidenemethyl)-benzenesulfonic acid and2-methyl-5-(2-oxo-3-bornylidene)-sulfonic acid and a salt thereof, andthe like. As the UV-A filter, a benzoylmethane derivative isparticularly used and, for example,1-(4′-t-butylphenyl)-3-(4′-methoxyphenyl)-propane-1,3-dione,4-t-butyl-4′-methoxydibenzoylmethane (Parsol (registered trade mark)1789), 1-phenyl-3-(4′-isopropylphenyl)-propane-1,3-dione, enaminecompound, and the like can be mentioned.

Examples of the hair-growth promoter include pantothenic acid and aderivative thereof, placenta extract, allantoin, and the like.

Examples of the whitening agent include arbutin, kojic acid, vitamin Cand a derivative thereof, and the like.

Examples of the antiperspirant and astringent active ingredient, andperspiration deodorant include salts of aluminum, zirconium and zincsuch as aluminum chloride, aluminum chlorohydrate, aluminum zirconiumtrichlorohydrate, aluminum zirconium tetrachlorohydrate, zincpyrrolidonecarboxylate, and the like.

Examples of the vitamin include vitamins A, B₁, B₂, B₆, E andderivatives thereof, and the like.

Examples of the vasodilator include swertia japonica extract,cepharanthine, and the like.

Examples of the crude drug include apricot extract, avocado extract,aloe extract, turmeric extract, orange extract, chamomilla extract, kiwiextract, ginkgo extract, tea extract, sage extract, swertia japonicaextract, Persicae Semen extract, rose extract, sunflower extract, grapeextract, loofah extract, peach leaf extract, eucalyptus extract,lavender extract, green tea extract, apple extract, lemon extract,rosemary extract, and the like.

Examples of the pH adjuster include citric acid, adipic acid, ascorbicacid, phosphoric acid, glutamic acid, lactic acid, sulfuric acid,hydrochloric acid, ammonium, sodium hydroxide, potassium hydroxide,arginine, hydroquinone and a derivative thereof, γ-oryzanol, and thelike.

Examples of the viscosity modifier include agar, organic modified claymineral and the like.

Examples of the pearly pigment include alkyleneglycol ester, fatty acidalkanolamide, fatty acid monoglyceride, fatty ether, and the like.

Examples of the natural perfume include flavor extracted from flowers(lily, lavender, rose, jasmine, etc.), stem and leaf (geranium,patchouli, etc.), fruit and fruit skin (lemon, orange, anise) and thelike, and the like.

Examples of the synthetic perfume include ester, ether, aldehyde,ketone, alcohol and hydrocarbon type flavor, and the like.

Examples of the dye include cochineal red A (C.I.16255), patent blue(C.I.42051), chlorophyllin (C.I.75810), and the like.

Examples of the antioxidant include tocopherol, sodium sulfite, and thelike.

Examples of the preservative include phenoxyethanol, paraben,pentanediol, and the like.

The emulsifier is, for example, a nonionic surfactant, and examplesthereof include an addition resultant product of 2 to 30 mol of ethyleneoxide and/or 0 to 5 mol of propylene oxide to straight chain fattyalcohol having 8 to 22 carbon atoms, fatty acid having 12 to 22 carbonatoms, alkylphenol wherein alkyl group has 8 to 15 carbon atoms, oralkylamine wherein alkyl group has 8 to 22 carbon atoms; alkyl and/oralkenyl oligoglycoside wherein alkyl(alkenyl) group has 8 to 22 carbonatoms, and an ethoxylated product thereof; ethylene oxide (1 to 15 mol)adduct of castor oil and/or hydrogenated castor oil; ethylene oxide (15to 60 mol) adduct of castor oil and/or hydrogenated castor oil; partialester of unsaturated straight chain or saturated branched fatty acidhaving 12 to 22 carbon atoms and/or hydroxycarboxylic acid having 3 to18 carbon atoms and glycerol and/or sorbitan, and adduct thereof with 1to 30 mol of ethylene oxide; partial ester of polyglycerol (2 to 8average degree of self-condensation), polyethylene glycol (molecularweight 400 to 5000), trimethylolpropane, pentaerythritol, sugar alcohol(for example, sorbitol), alkyl glucoside (for example, methyl glucoside,butyl glucoside, lauryl glucoside) and/or polyglucoside (for example,cellulose), and saturated and/or unsaturated straight chain or branchedfatty acid having 12 to 22 carbon atoms and/or hydroxycarboxylic acidhaving 3 to 18 carbon atoms, and adduct thereof with 1 to 30 mol ofethylene oxide; mixed ester of pentaerythritol, fatty acid, mixed esterof citric acid and fatty alcohol, and/or fatty acid having 6 to 22carbon atoms, and methyl glucose and polyol (preferably glycerol orpolyglycerol); mono-, di-, trialkylphosphate and mono-, di- and/ortri-PEG-alkylphosphate and a salt thereof; wool wax alcohol;polysiloxane/polyalkyl/polyether copolymer and the correspondingderivative; block copolymer (e.g., polyethylene glycol-30dipolyhydroxystearate); polymer emulsifier (e.g., Goodrich Pemulen type(TR-1, TR-2)); polyalkylene glycol, and glycerol carbonate and the like.Examples of ethylene oxide adduct include ethylene oxide of fattyalcohol, fatty acid, alkylphenol or castor oil, and examples ofpropylene oxide adduct include known, commercially available products.Examples of partial glyceride include hydroxystearic acid monoglyceride,hydroxystearic acid diglyceride, isostearic acid monoglyceride,isostearic acid diglyceride, oleic acid monoglyceride, oleic aciddiglyceride, ricinoleic acid monoglyceride, ricinoleic acid diglyceride,linoleic acid monoglyceride, linoleic acid diglyceride, linolenic acidmonoglyceride, linolenic acid diglyceride, erucic acid monoglyceride,erucic acid diglyceride, tartaric acid monoglyceride, tartaric aciddiglyceride, citric acid monoglyceride, citric acid diglyceride, malicacid monoglyceride, malic acid diglyceride and the like. Moreover,ethylene oxide 1 to 30 mol (preferably 5 to 10 mol) adduct of theabove-mentioned partial glyceride is also suitable. Examples of sorbitanester include sorbitan monoisostearate, sorbitan sesquiisostearate,sorbitan diisostearate, sorbitan triisostearate, sorbitan monooleate,sorbitan sesquioleate, sorbitan dioleate, sorbitan trioleate, sorbitanmonoerucate, sorbitan sesquierucate, sorbitan dierucate, sorbitantrierucate, sorbitan monoricinolate, sorbitan sesquiricinolate, sorbitandiricinolate, sorbitan triricinolate, sorbitan monohydroxystearate,sorbitan sesquihydroxystearate, sorbitan dihydroxystearate, sorbitantrihydroxystearate, sorbitan monotartrate, sorbitan sesquitartrate,sorbitan ditartrate, sorbitan tritartrate, sorbitan monocitrate,sorbitan sesquicitrate, sorbitan dicitrate, sorbitan tricitrate,sorbitan monomaleate, sorbitan sesquimaleate, sorbitan dimaleate,sorbitan trimaleate, and industrial mixtures thereof. In addition,ethylene oxide 1 to 30 mol (preferably 5 to 10 mol) adduct of theabove-mentioned sorbitan ester is also suitable. Examples ofpolyglycerol ester include polyglyceryl-2 dipolyhydroxystearate(Dehymuls (registered trade mark) PGPH), polyglyceryl-3 diisostearate(Lameform (registered trade mark) TGI), polyglyceryl-4 isostearate(Isolan (registered trade mark) GI 34), polyglyceryl-3 oleate,diisostearoyl polyglyceryl-3 diisostearate (Isolan (registered trademark) PDI), polyglyceryl-3 methylglucose distearate (Tego Care(registered trade mark) 450), polyglyceryl-3 beeswax (Cera Bellina(registered trade mark)), polyglyceryl-4 caprate (Polyglycerol CaprateT2010/90), polyglyceryl-3 cetyl ether (Chimexane (registered trade mark)NL), polyglyceryl-3 distearate (Cremophor (registered trade mark) GS 32)and polyglyceryl polyricinolate (Admul (registered trade mark) WOL1403), polyglyceryl dimerate isostearate, mixtures thereof and the like.Examples of polyol ester include mono-, di- and tri-ester oftrimethylolpropane or pentaerythritol and lauric acid, palm oil fattyacid, tallow fatty acid, palmitic acid, stearic acid, oleic acid,behenic acid and the like, which may be reacted with ethylene oxide (1to 30 mol) where necessary.

Examples of the fat and wax include 12-hydroxystearic acid, lanolin,beeswax, candelilla wax, carnauba wax and the like.

Examples of the silicone compound include dimethylpolysiloxane,methylphenylpolysiloxane, cyclic silicone, amino-, fatty acid-,alcohol-, polyether-, epoxy-, fluorine-, glycoside- and/oralkyl-modified silicone compound (which can be liquid or resin-like atroom temperature), simethicone which is a mixture of dimethicone havingan average chain length of dimethyl siloxane unit number of 200 to 300and silicate hydride, and the like.

Examples of the balm include a mixture of natural and synthetic flavor.Examples of the natural flavor include plant-derived starting materialssuch as flower (lily, lavender, rose, jasmine, neroli, ylang-ylang),stem and leaf (geranium, patchouli, petitgrain), fruit (anise, cilantro,caraway, juniper), fruit skin (bergamot, lemon, orange), root (nutmeg,angelica, celery, cardamom, costus, irid, calamus), tree (pine,sandalwood, guaiac, cedar, red sandalwood), herb and grass (tarragon,lemongrass, sage, thyme), acerose leaf and branch (spruce, fir, pine,scrub pine), resin and balsam (galbanum, elemi, benzoin, myrrh,frankincense, opopanax) and the like, and animal-derived startingmaterials such as civet, beaver, and the like. Examples of thecomparatively low volatile essential oil often used as an aromaticcomponent include sage oil, chamomile oil, clove oil, Melissaofficinalis oil, mint oil, cinnamon leaf oil, lime flower oil, juniperberry oil, vetiver oil, balm, galbanum oil, labdanum oil and lavandinoil, bergamot oil, dihydromyrcenol, lilial, lyral, citronellol,phenylethyl alcohol, α-hexylcinnam aldehyde, geraniol, benzylacetone,cyclamenaldehyde, linalool, Boisambrene Forte, Ambroxan, indole,Hedione, Sandelice, citrus oil, mandarin oil, orange oil, allylpentylglycholate, Cyclovertal, lavandin oil, clary oil, β-damascone, geraniumoil bourbon, cyclohexyl salicylate, Vertofix Coeur, Iso-E-Super,Fixolide NP, evernyl, Iraldein gamma, phenylacetic acid, geranylacetate, benzyl acetate, rose oxide, Romilat, Irotyl and Floramat,peppermint oil, spearmint oil, anise oil, illicium verum oil, carawayoil, eucalyptus oil, fennel oil, citrus oil, wintergreen oil, clove oil,menthol, and the like.

In another embodiment of the present invention, the cysteine derivativeof the present invention may be used as a cysteine substitute for foodor drink such as nutritional supplement, supplement, health food,modified powdered milk for infants and the like, or a pharmaceuticalproduct such as infusion, dye deposition improving drug and the like.Besides these, for example, it can also be used as a flavor startingmaterial or an antioxidant. The amount thereof to be added can beappropriately determined as in the case of cosmetic agents.

The production method of the cysteine derivative represented by theabove-mentioned formula (I) (hereinafter sometimes to be abbreviated ascysteine derivative (I)) is not particularly limited and known methodscan be combined for the production. Specifically, the synthesis iscarried out by the following method, but the method is not limitedthereto.

Compound (IV) which is a precursor of cysteine derivative (I) can besynthesized according to the following Production Method 1 or 2, andthen cysteine derivative (I) can be synthesized Production Method 3.Compound (IV) may or may not be purified as necessary.

Production Method 1.

Method of obtaining compound (IV) by reacting cysteine, or a compoundrepresented by the formula (II) (hereinafter to be abbreviated ascompound (II), the same for compounds represented by other formulas),which is obtained by subjecting cysteine to esterification or amidationin advance, with compound (III) and forming a ring:

wherein each symbol is as defined above.

Compound (IV) is obtained by reacting compound (II) with compound (III)in water or an alcohol such as methanol, ethanol and the like for 5 to24 hours. Of compound (II), cysteine ethyl ester can be obtained, forexample, by reacting cysteine in the presence of hydrochloric acid orthionyl chloride, in ethyl alcohol, at room temperature for about 5 to24 hours. Of compound (II), cysteinamide is obtained by reacting aprotected cysteine with an amine in the presence of a dehydratingcondensing agent such as EDCI HCl(1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride), in asolvent such as methylene chloride and N,N-dimethylformamide (DMF), atroom temperature for 5 to 24 hours, and then deprotecting the obtainedcompound.

Production Method 2.

A method of reacting cysteine (VII) with compound (VIII) to synthesizecompound (IV″) which is a thiazolidine derivative, and then, wherenecessary, subjecting the two carboxyl group of compound (IV″) toesterification or amidation to synthesize compound (IV):

wherein each symbol is as defined above.

Compound (IV) can be obtained by reacting cysteine (VII) with compound(VIII) in water or an alcohol such as methanol, ethanol and the like for5 to 24 hours to synthesize compound (IV″), and then, where necessary,reacting the carboxyl group of compound (IV″) under conditions similarto that in the esterification or amidation of cysteine in ProductionMethod 1.

Production Method 3.

wherein A is a halogen atom, and other symbols are as defined above.

Cysteine derivative (I) can be synthesized by reacting compound (IV)with compound (V) or compound (V′) in the presence or absence of asolvent, in the presence or absence of a base. Examples of the solventinclude THF (tetrahydrofuran), ethyl acetate, isopropyl acetate,acetonitrile, acetone, ethanol, methanol, dichloromethane, water, amixture thereof, and the like, and THF, ethyl acetate, isopropylacetate, acetonitrile, acetone, dichloromethane, water, and a mixturethereof are preferable. Examples of the base include organic bases suchas triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine,and the like, inorganic bases such as lithium hydroxide, sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,sodium acetate, potassium acetate and the like, and triethylamine,diisopropylethylamine, pyridine, N-methylmorpholine, potassiumcarbonate, sodium carbonate are preferable.

The amount of compound (V) or compound (V′) to be used is 1.0 to 5.0mol, preferably 1.2 to 3.0 mol, per 1 mol of compound (IV). When a baseis used, the amount of the base to be used is 1.0 to 5.0 mol, preferably1.2 to 4.0 mol, per 1 mol of compound (IV). The reaction temperature is−10 to 100° C., preferably 0 to 90° C. The reaction time is 1 hour to 48hours, preferably 3 hours to 20 hours.

Cysteine derivative (I) may be converted to other cysteine derivative(I) by esterification, amidation, hydrolysis or acid anhydride formationor the like. For example, when X or/and Y is OH, cysteine derivative (I)wherein the carboxyl group is amidated by an optionally modified aminoacid residue can be obtained by reacting cysteine derivative (I) with anamino acid, an amino acid ester or a salt thereof (preferablyhydrochloride) or an amino acid amide using a dehydrating condensingagent such as EDCI HCl and the like in the presence of a base, asnecessary, in an organic solvent. For promotion of the reaction, HOBtH₂O (1-hydroxybenzotriazole hydrate) and the like may be added for thisreaction. Examples of the base include triethylamine,diisopropylethylamine, and the like. Examples of the organic solventinclude dichloromethane, chloroform, THF, DMF, ethyl acetate, and thelike. Where necessary, the ester group, amide group or the like of themodified amino acid residue may be deprotected. The reaction conditionsof the dehydrating condensation and the like can be conditions generallyemployed in peptide synthesis.

In addition, by appropriately selecting reaction conditions for theproduction of cysteine derivative (I) from compound (IV), the trans formor cis form of cysteine derivative (I) can be selectively produced. Forexample,

a) a trans form of cysteine derivative (I) wherein X is a hydroxyl groupand Y is a C₁₋₂₂ alkoxy group (i.e., cysteine derivative (I′)) can beselectively produced by reacting compound (IV) wherein X is a hydroxylgroup and Y is a C₁₋₂₂ alkoxy group (i.e., compound (IV′)) with compound(V) in the presence of an organic base, or with compound (V′) in theabsence of a base,

b) a cis form of cysteine derivative (I) wherein X and Y are hydroxylgroups can be selectively produced by reacting compound (IV) wherein Xand Y are hydroxyl groups, with compound (V′) in the absence of a base.

A cis form-trans form mixture or cis form of cysteine derivative (I) isobtained by reacting compound (IV) with compound (V) or compound (V′) inthe presence of an inorganic base. The ratio of cis form:trans form ofthe resultant product by these reaction varies depending on the ratio ofcis form:trans form of compound (IV).

In the production method by the above-mentioned a), examples of theorganic base include triethylamine, pyridine, N-methylmorpholine,diisopropylethylamine, and the like, and triethylamine is preferable.This reaction can be carried out in the presence or absence of asolvent. Examples of the solvent include ethyl acetate, isopropylacetate, tetrahydrofuran, acetone, and the like, and ethyl acetate ispreferable. The amount of compound (V) or compound (V′) to be used is1.0 to 5.0 mol, preferably 1.2 to 3.0 mol, per 1 mol of compound (IV).When a base is used, the amount of the base to be used is 1.0 to 5.0mol, preferably 1.2 to 4.0 mol, per 1 mol of compound (IV). The reactiontemperature is −10 to 100° C., preferably 0 to 90° C. The reaction timeis 1 to 48 hours, preferably 3 to 20 hours.

The “selective” production of trans form or cis form means that theratio of trans form or cis form of the whole of the obtained cysteinederivative (I) is generally 70% or more, preferably 85% or more, morepreferably 90% or more.

As mentioned above, since cysteine derivative (I) is preferably a transform from the aspects of stability, it is preferably synthesized byproduction method a). The trans form of cysteine derivative (I)synthesized by production method a) can be converted to the trans formof other cysteine derivative (I) (e.g., X, Y═OH) by hydrolysis and thelike.

Production Method 4.

wherein each symbol is as defined above.

Cysteine derivative (I) can be synthesized by reacting compound (VI),which is N-acylated-, N-alkoxycarbonylated- orN-alkylcarbamoylated-cysteine derivative, with compound (III). Cysteinederivative (I) may be converted to other cysteine derivative (I) byesterification, amidation, hydrolysis or the like.

Cysteine derivative (IX) can be produced according to theabove-mentioned production method of cysteine derivative (I).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments which are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

When plural isomers are contained as resultant products, the isomer tobe the main resultant product was subjected to NMR measurement. Themeasurement was performed using Bruker AVANCE 400 manufactured byBruker. The cis form and trans form was determined by an X ray crystalstructure analysis of each crystal.

Reference Example 1 2-methylthiazolidine-2,4-dicarboxylic acid(cysteinylpyruvic acid; hereinafter sometimes to be abbreviated as CP inthe present specification)

Under an argon atmosphere, L-cysteine (15 g) was dissolved in dryethanol (35 mL), pyruvic acid (18.6 mL) was added thereto at roomtemperature, and the mixture was stirred for 3 hours. The resultingsolid was collected by filtration under reduced pressure, and washedwith ice-cooled ethanol to give 2-methylthiazolidine-2,4-dicarboxylicacid (diastereomer mixture) (23 g, yield 97%).

¹H-NMR (DMSO-d₆) δ; 1.59 (3H, s), 1.72 (3H, s), 2.76 (1H, dd), 2.97 (1H,dd), 3.26 (1H, dd), 3.40 (1H, dd), 3.98 (1H, dd), 4.19 (1H, dd); MSspectrum m/z; 190 (M).

Reference Example 2 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethylester (hereinafter sometimes to be abbreviated as CP2Et in the presentspecification)

Under an argon atmosphere, L-cysteine (10 g) was dissolved in pure water(150 ml), and ethyl pyruvate (19.7 ml) dissolved in ethanol (10 ml) atroom temperature was gradually added to the solution. The mixture wasstirred overnight at room temperature, and concentrated under reducedpressure. The obtained solid was dissolved in pure water, and thesolution was extracted with chloroform. The extract was dried overmagnesium sulfate, and concentrated under reduced pressure to give anoil. The oil was recrystallized from chloroform/hexane to give2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (diastereomermixture) (12.7 g, yield 70%).

¹H-NMR (DMSO-d₆) δ; 1.19 (3H, t), 1.23 (3.9H, t), 1.62 (3H, s), 1.75(3H, s), 1.75 (3H, s), 2.81 (1.3H, t), 2.97 (1H, dd), 3.29 (1H, dd),3.42 (1.3H, dd), 4.03 (1.3H, dd), 4.09 (2H, m), 4.16 (1H, dd), 4.20(2.6H, q); MS spectrum m/z; 220 (M⁺).

Synthetic Example 1 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester (hereinafter sometimes to be abbreviated as N-Ac-CP2Et inthe present specification)

2-Methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (10.0 g, 45.6mmol) obtained by a method similar to that in Reference Example 2 wasdissolved in THF (100 ml), and the solution was kept at 0° C. To thesolution was added triethylamine (12.7 ml, 91.2 mmol), and acetylchloride (6.5 ml, 91.2 mmol) was added dropwise thereto over 10 minutes.The reaction temperature was allowed to gradually rise, and the mixturewas stirred overnight at room temperature. The reaction mixture wasconcentrated under reduced pressure. To the residue was added ethylacetate, and the mixture was washed with water. The ethyl acetate layerwas washed with 5% aqueous citric acid, 5% aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (eluted with ethyl acetate-5% aceticacid) to give N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester (trans form) as a pale-brown oil (7.7 g, 64.6%).

¹H-NMR (CDCl₃): δ; 1.27 (3H, t, J=7.12 Hz), 1.94 (3H, s), 2.18 (3H, s),3.40 (1H, d, J=11.6 Hz), 3.56 (1H, dd, J=5.5, 11.0 Hz), 4.20 (2H, t,J=7.08 Hz), 5.00 (1H, d, J=5.9 Hz), 9.10 (1H, brs).

Synthetic Example 2 Crystal ofN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester

The crude product of N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester (10.28 g, oil) obtained by a method similar to that inSynthetic Example 1 was purified by silica gel column chromatography(eluent: ethyl acetate:acetic acid=95:5, volume ratio), and the fractionwas concentrated under reduced pressure. To the residue was addedtoluene, and the mixture was concentrated under reduced pressure to givean amorphous pale-yellow substance. The substance was recrystallizedfrom ethyl acetate and n-hexane to giveN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (transform) as pale-yellow crystals (7.0 g, about 59%).

¹H-NMR (DMSO-d₆): δ; 1.15 (3H, t, J=7.08 Hz), 1.77 (3H, s), 2.03 (3H,s), 5.33 (1H, d, J=4.64 Hz).

Synthetic Example 3 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester

2-Methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (2.00 g, 9.14mmol) obtained by a method similar to that in Reference Example 2 wasdissolved in ethyl acetate (20 ml), and the solution was kept at 0° C.To the solution was added pyridine (1.48 ml, 18.3 mmol), and acetylchloride (0.97 ml, 13.7 mmol) was added dropwise thereto. The reactiontemperature was allowed to gradually rise, and the mixture was stirredat room temperature for 4 hours. To the reaction mixture was added 5%aqueous citric acid, and the mixture was extracted with ethyl acetate.The extract was washed with water and saturated brine, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure togive N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester(with the ratio of trans form of about 75% as confirmed by NMR) as apale-brown oil (2.02 g).

Synthetic Example 4 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester

By an operation similar to that in Synthetic Example 3 except for theuse of N-methylmorpholine (2.01 ml, 18.3 mmol) instead of pyridine,N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (withthe ratio of trans form of about 80% as confirmed by NMR) was obtainedas a pale-brown oil (1.93 g).

Synthetic Example 5 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester

By an operation similar to that in Synthetic Example 3 except for theuse of diisopropylethylamine instead of pyridine,N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (withthe ratio of trans form of about 90% as confirmed by NMR) was obtainedas a orange-yellow oil.

Synthetic Example 6 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester

By an operation similar to that in Synthetic Example 3 except thatpotassium carbonate (2.54 g, 18.4 mmol) was used instead of pyridine andthe mixture was stirred for 16 hours instead of 4 hours,N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (withthe ratio of cis form:trans form of about 47:53 as confirmed by NMR) wasobtained as a colorless oil (0.895 g).

Synthetic Example 7 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester

By an operation similar to that in Synthetic Example 6 except for theuse of 2N HCl instead of 5% aqueous citric acid,N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester wasobtained as a pale-yellow oil. To the oil was added n-hexane, and themixture was concentrated under reduced pressure. To the residue wasn-hexane to allow solidification of the residue. The solid was collectedby filtration, and dried under reduced pressure to give a crystal ofN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (withthe ratio of cis form:trans form of about 50:50 as confirmed by NMR) wasobtained (22.33 g).

¹H-NMR (CDCl₃, 400 MHz): δ:

trans: 1.29 (3H, t, J=7.11 Hz), 1.96 (3H, s), 2.19 (3H, s), 3.42 (1H, d,J=11.7 Hz), 3.60 (1H, dd, J=6.28, 11.8 Hz), 4.16-4.29 (2H, m), 5.03 (1H,d, J=5.97 Hz).

cis: 1.38 (3H, t, J=7.13 Hz), 1.95 (3H, s), 2.16 (3H, s), 3.47 (1H, dd,J=1.66, 12.2 Hz), 3.72 (1H, dd, J=6.79, 12.2 Hz), 4.33-4.48 (2H, m),4.98 (1H, dd, J=1.68, 6.78 Hz).

Synthetic Example 8 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester

By a method similar to that in Synthetic Example 7 except for the use of2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester synthesizedfrom D-cysteine by a method similar to that in Reference Example 2,N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester wasobtained (with the ratio of cis form:trans form of about 43:57 asconfirmed by NMR).

Synthetic Example 9 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester

2-Methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (1.00 g, 4.59mmol) obtained by a method similar to that in Reference Example 2 wasdissolved in ethyl acetate (10 ml), and the solution was kept at 0° C.To the solution was added dropwise acetic anhydride (1.29 ml, 13.7mmol), and the reaction mixture was heated under reflux for 3 hours. Thereaction mixture was concentrated under reduced pressure, toluene wasadded thereto, and the mixture was concentrated under reduced pressure.To the residue was added ethyl acetate, and the mixture was washed withwater and saturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. To the residue was added water, andthe mixture was stirred. Water was removed by decantation, and theresidue was concentrated under reduced pressure. To the residue wereadded ethyl acetate and n-hexane to allow solidification of the residue.The solid was collected by filtration, and dried under reduced pressureto give N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethylester (trans form) (0.56 g).

Synthetic Example 10 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester

L-Cysteine hydrochloride monohydrate (100 g, 569 mmol) was dissolved inwater (200 ml), and the pH of the solution was adjusted to 5.07 with 6Naqueous sodium hydroxide. The reaction mixture was heated to 40° C.,ethyl pyruvate (76 ml, 684 mmol) was gradually added thereto, and themixture was stirred at 40° C. for 3.5 hours to give2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio oftrans form:cis form of the resultant product in the reaction mixture wasconfirmed by the area ratio of an HPLC chart to find about 55:45). Aftercompletion of the reaction, the reaction mixture was extracted withethyl acetate. The extract was washed with saturated brine, and driedover anhydrous magnesium sulfate. To the obtained ethyl acetate solutionwas added triethylamine (159 ml, 1141 mmol) under argon, and acetylchloride (61 ml, 858 mmol) was slowly added dropwise thereto. Thereaction mixture was heated under reflux for 4 hr to giveN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (theratio of trans form:cis form of the resultant product in the reactionmixture was confirmed by the area ratio of an HPLC chart to find about95:5). After completion of the reaction, water (100 ml) was addedthereto, and the pH of the mixture was adjusted to 2.5 with HCl. Theaqueous layer was separated, and extracted with ethyl acetate. Theextract was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The obtained ethyl acetate solution was concentrateduntil a weight of 900 g, to the residue was added heptane to allowrecrystallization of the residue, and the crystals were washed withheptane/ethyl acetate=2/1, and dried at 50° C. under reduced pressure togive a crystal of a trans form ofN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (theratio of trans form:cis form of the resultant product in the reactionmixture was confirmed by the area ratio of an HPLC chart to find about99%) (84 g, yield 57%). The melting point of the obtained crystal wasmeasured using digital melting point measuring apparatus IA9100manufactured by Electrothermal to be 138° C. to 141° C.

Synthetic Example 11 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester

D-Cysteine hydrochloride monohydrate (10 g, 57 mmol) was dissolved inwater (20 ml), and the pH of the solution was adjusted to 5.13 with 6Naqueous sodium hydroxide solution. The reaction mixture was heated to40° C., ethyl pyruvate (7.6 ml, 68 mmol) was gradually added thereto,and the mixture was stirred at 40° C. for 4.5 hours to give2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio oftrans form:cis form of the resultant product in the reaction mixture wasconfirmed by NMR to find about 55:45). After completion of the reaction,the reaction mixture was extracted with ethyl acetate. The extract waswashed with saturated brine, and dried over magnesium sulfate. To theobtained ethyl acetate solution was added triethylamine (16 ml, 115mmol) under argon, acetyl chloride (6.1 ml, 86 mmol) was slowly addeddropwise thereto, and the reaction mixture was heated under reflux for 3hr to give N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethylester (the ratio of trans form:cis form of the resultant product in thereaction mixture was confirmed by NMR to be about 97:3). Aftercompletion of the reaction, water (30 ml) was added thereto, and the pHof the mixture was adjusted to 0.9 with 5.7M HCl. The aqueous layer wasseparated, and extracted with ethyl acetate. The extract was washed withsaturated brine, and dried over anhydrous magnesium sulfate. Theobtained ethyl acetate solution was concentrated to a weight of 157 g,and to the residue was heptane to be recrystallize the residue. Thesolid was washed with heptane/ethyl acetate=1.5/1, and dried at 50° C.under reduced pressure to give a crystal of a trans form ofN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (theratio of the trans form was confirmed by the area ratio of an HPLC chartto find about 99%) (10.7 g, yield 71%).

-   HPLC analysis conditions in Synthetic Examples 10 and 11 and the    following Synthetic Example 41-   detector: ultraviolet absorption spectrophotometer (measurement    wavelength; 210 nm)-   column: YMC-Pack ODS-A (particle size 5 μm, fine pore size 12 mm,    inner diameter 6.0 mm, length 150 mm)-   eluent: 50 mM NaH₂PO₄ (adjusted to pH 2 with 85% H₃PO₄): MeOH=60:40-   flow rate: 1.0 mL/minute-   column temperature: 40° C.-   injection volume: 10 μL-   retention time (min): CP2Et (cis form): 9.0, CP2Et (trans form):    8.6, N-Ac-CP2Et (cis form): 7.5, (trans form): 9.2

Synthetic Example 12 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester Na salt

The crude product (2.01 g, oil) ofN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, whichwas obtained by a method similar to that in Synthetic Example 1, wasdissolved in ethanol (15 ml), and 4N NaOH (1.54 ml, about 6.2 mmol) wasadded thereto. The mixture was stirred at room temperature for 2.5hours, and concentrated under reduced pressure to give an amorphoussubstance. This was dried under reduced pressure to giveN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester Nasalt (trans form) as a pale-yellow powder (1.95 g, about 89%).

¹H-NMR (D₂O): δ; 1.17 (3H, t), 1.78 (3H, s), 2.05 (3H, s), 3.32 (1H, d,J=11.8 Hz), 4.12 (2H, t), 4.93 (1H, d, J=5.68 Hz).

Synthetic Example 13 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid(N-acetyl-cysteinylpyruvic acid; hereinafter sometimes to be abbreviatedas N-Ac-CP)

N-Acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl esterobtained by an operation similar to that in Synthetic Example 1 wasdissolved in a mixed solvent of methanol (120 ml) and water (120 ml),and 2N NaOH (182.4 ml) was added thereto. The reaction mixture washeated with stirring under an argon atmosphere at 100° C. for 4 hours,and then at 80° C. overnight. The reaction mixture was allowed to coolto room temperature, and the pH was adjusted to 1 to 2 with AMBERLITEIR120B H AG (about 250 g). The AMBERLITE was removed by filtration, andthe filtrate was concentrated under reduced pressure. To the residue wasethyl acetate (200 ml), the mixture was stirred for 1 hour, and theresulting white crystals were collected by filtration to giveN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid (trans form) (15.99g, 75%).

¹H-NMR (DMSO-d₆): δ; 1.73 (3H, s), 2.01 (3H, s), 3.36 (2H, d, J=3.6 Hz),5.26 (1H, t, J=3.6 Hz); MS spectrum m/z; [M+H]⁺=234.0, [M−H]⁻=232.0.

Synthetic Example 14 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2Na salt

The crude product (10.19 g) ofN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester, whichwas obtained by a method similar to that in Synthetic Example 13, wasdissolved in ethanol (20 ml), and 4N NaOH was added thereto. The mixturewas stirred under an argon atmosphere, and ethanol was added thereto togive a pale-yellow solid. The obtained solid was collected by filtrationto give N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2Na salt(trans form) as crystals (9.09 g, about 72%).

¹H-NMR (D₂O): δ; 1.73 (3H, s), 2.01 (3H, s), 3.15 (1H, d, J=11.4 Hz),3.39 (1H, dd, J=6.6, 11.7 Hz), 4.80 (1H, d, J=6.5 Hz).

Synthetic Example 15 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid

By an operation similar to that in Synthetic Example 13 and using2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester synthesizedfrom DL-cysteine by a method similar to that in Reference Example 2,N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid (trans form) wasobtained as a white solid (yield 70%).

Synthetic Example 16 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid

2-Methylthiazolidine-2,4-dicarboxylic acid (20 g, 104.6 mmol) obtainedby a method similar to that in Reference Example 1 and acetic anhydride(40 ml, 418.3 mmol) were heated at 100° C. for 2 hours. The reactionmixture was concentrated under reduced pressure, 5% aqueous citric acid(200 ml) was added thereto, and the mixture was stirred overnight atroom temperature. Concentrated hydrochloric acid (2 ml) was addedthereto, and the mixture was stirred at 70° C. for 1 hour. The reactionmixture was filtered off to remove tar substance, and the filtrate wasconcentrated under reduced pressure to a volume of about 100 ml. Themixture was extracted with ethyl acetate. The extract was washed withsaturated brine, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to giveN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid (16.3 g) as anamorphous substance. To the amorphous substance was added water to allowrecrystallization of the substance, and the obtained crystals were driedunder reduced pressure to giveN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid (cis form) as awhite solid (5.3 g, 23%).

¹H-NMR (DMSO-d₆): δ; 1.80 (3H, s), 2.02 (3H, s), 3.49 (1H, dd, J=1.04,12.00 Hz), 3.61 (1H, dd, J=6.30, 12.00 Hz), 5.22 (1H, dd, J=6.24, 1.04);MS spectrum m/z; [M+H]⁺=234.0, [M−H]⁻=232.0.

Synthetic Example 17 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid

By an operation similar to that in Synthetic Example 16 and using2-methylthiazolidine-2,4-dicarboxylic acid synthesized from DL-cysteineby a method similar to that in Reference Example 1,N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid (cis form) wasobtained as an amorphous substance (yield 44%).

Synthetic Example 18 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acidanhydride

2-Methylthiazolidine-2,4-dicarboxylic acid (2.0 g, 10.5 mmol) obtainedby a method similar to that in Reference Example 1 and acetic anhydride(4.0 ml, 42.0 mmol) were heated at 100° C. for 2 hours. The reactionmixture was concentrated under reduced pressure, and the residue wasextracted with ethyl acetate. The extract was washed with saturatedbrine, dried over anhydrous magnesium sulfate, and concentrated underreduced pressure to give N-acetyl-2-methylthiazolidine-2,4-dicarboxylicacid anhydride (2.12 g) as an amorphous substance. The amorphoussubstance was purified by silica gel chromatography (eluted withn-hexane-ethyl acetate) to giveN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid anhydride (cis form)as a white solid (1.2 g, 53%).

¹H-NMR (DMSO-d₆): δ; 1.78 (3H, s), 1.89 (3H, s), 3.63 (1H, dd, J=0.84,12.64 Hz), 3.86 (1H, dd, J=5.76, 12.64 Hz), 4.91 (1H, dd, J=0.92, 5.72).

Synthetic Example 19 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2,4-diethyl ester

N-Acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (1.5g, 5.74 mmol) obtained by a method similar to that in Synthetic Example1 was dissolved in dichloromethane (30 ml), and the reaction mixture waskept at 0° C. To the solution were added ethanol (0.40 ml, 6.89 mmol),EDCI HCl (1.32 g, 6.89 mmol) and DMAP (4-dimethylaminopyridine, 0.14 g,1.15 mmol). The reaction temperature was allowed to gradually rise from0° C., and the mixture was stirred overnight at room temperature. Thereaction mixture was concentrated under reduced pressure, to the residuewas added ethyl acetate, and the mixture was washed with water. Theethyl acetate layer was washed with 5% aqueous citric acid, 5% aqueoussodium hydrogen carbonate and saturated brine, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure to giveN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester(trans form) as a pale-brown oil (0.69 g, 41.3%).

¹H-NMR (CDCl₃): δ; 1.27 (3H, t, J=7.12 Hz), 1.33 (3H, t, J=7.16 Hz),1.93 (3H, s), 2.12 (3H, s), 3.36 (1H, dd, J=0.52, 11.68 Hz), 3.54 (1H,dd, J=6.16, 11.64 Hz), 4.12-4.25 (2H, m), 4.25-4.33 (2H, m), 4.95 (1H,d, J=5.84 Hz).

Synthetic Example 20 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl 4-isopropyl ester

N-Acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (1.5g, 5.74 mmol) obtained by a method similar to that in Synthetic Example1 was dissolved in dichloromethane (30 ml), and the reaction mixture waskept at 0° C. To the solution were added isopropanol (0.53 ml, 6.89mmol), EDCI HCl (1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride, 1.32 g, 6.89 mmol), and DMAP (0.14 g, 1.15 mmol). Thereaction temperature was allowed to gradually rise from 0° C., and themixture was stirred overnight at room temperature. The reaction mixturewas concentrated under reduced pressure, to the residue was added ethylacetate, and the mixture was washed with water. The ethyl acetate layerwas washed with 5% aqueous citric acid, 5% aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate,and concentrated under reduced pressure to giveN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl 4-isopropylester (trans form) as a pale-brown oil (0.68 g, 39.0%).

¹H-NMR (CDCl₃): δ; 1.12-1.17 (9H, m), 1.93 (3H, s), 1.96 (3H, s), 3.35(1H, d, J=11.4 Hz), 3.53 (1H, dd, J=6.3, 11.4 Hz), 4.14-4.29 (2H, m),4.90 (1H, d, J=6.0 Hz), 5.14 (1H, q, J=6.0 Hz).

Synthetic Example 21N-tert-butoxycarbonyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethylester

2-Methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (1.1 g, 5.02mmol) obtained by a method similar to that in Reference Example 2 wasdissolved in THF (10 ml), and the reaction mixture was kept at 0° C. Tothe solution were added (Boc)₂O (di-t-butyl dicarbonate, 1.3 g, 6.02mmol), and triethylamine (0.77 ml, 5.52 mmol). The reaction temperaturewas allowed to gradually rise from 0° C., and the mixture was stirredovernight at room temperature. To the reaction mixture was added DMAP(0.30 g, 2.50 mmol), and the mixture was stirred at room temperature foradditional 6 hours. The reaction mixture was concentrated under reducedpressure, to the residue was added ethyl acetate, and the mixture waswashed with water. The ethyl acetate layer was washed with 5% aqueouscitric acid, 5% aqueous sodium hydrogen carbonate and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure to giveN-tert-butoxycarbonyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethylester (with the ratio of cis form:trans form of about 50:50 as confirmedby NMR) as a pale-yellow oil (1.00 g, 62.4%).

¹H-NMR (CDCl₃): δ; 1.24-1.32 (9H, m), 1.97 (1.5H, d, J=6.84 Hz), 2.05(1.5H, s), 3.26-3.52 (2H, m), 4.15-4.30 (2H, m), 4.78-4.90 (1H, m).

Synthetic Example 22 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester 4-glycine ethyl ester amide

N-Acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (0.200g, 0.77 mmol) obtained by a method similar to that in Synthetic Example1 was dissolved in dichloromethane (2 ml), and the reaction mixture waskept at 0° C. To the solution were added glycine ethyl esterhydrochloride (0.107 g, 0.77 mmol), triethylamine (0.120 ml, 0.87 mmol),HOBt H₂O (1-hydroxybenzotriazole hydrate, 0.113 g, 0.84 mmol), and EDCIHCl (0.161 g, 0.84 mmol). The reaction temperature was allowed togradually rise from 0° C., and the mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated under reducedpressure, to the residue was added ethyl acetate, and the mixture waswashed with water. The ethyl acetate layer was washed with 5% aqueouscitric acid, 5% aqueous sodium hydrogen carbonate and saturated brine,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure to give N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester 4-glycine ethyl ester amide (trans form) as a white solid(0.211 g, 80.0%).

¹H-NMR (CDCl₃): δ; 1.22-1.32 (6H, m), 2.05 (3H, s), 2.19 (3H, s), 3.35(1H, d, J=11.84 Hz), 3.60 (1H, dd, J=6.96, 11.88 Hz), 4.12 (2H, t,J=5.08 Hz), 4.15-4.26 (4H, m), 4.88 (1H, d, J=6.8 Hz), 6.85 (1H, brs).

Synthetic Example 23 N-decanoyl-2-methylthiazolidine-2,4-dicarboxylicacid 2-ethyl ester

2-Methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester obtained by amethod similar to that in Reference Example 2 was subjected to acylationwith decanoyl chloride in the presence of triethylamine, and the mixturewas purified by silica gel chromatography to giveN-decanoyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester(trans form) as white crystals (91.9%).

¹H-NMR (CDCl₃, 400 MHz): δ; 0.89 (3H, t, J=6.86 Hz), 1.28 (3H, t, J=7.10Hz), 1.19-1.33 (12H, m), 1.61-1.68 (2H, m), 1.95 (3H, s), 2.30-2.34 (2H,m), 3.41 (1H, d, J=11.7 Hz), 3.58 (1H, dd, J=6.26, 11.7 Hz), 4.18-4.24(2H, m), 5.06 (1H, d, J=5.98 Hz).

Synthetic Example 24 N-decanoyl-2-methylthiazolidine-2,4-dicarboxylicacid

N-Decanoyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl esterobtained by a method similar to that in Synthetic Example 23 wassubjected to hydrolysis with sodium hydroxide (water-ethanol solvent) togive N-decanoyl-2-methylthiazolidine-2,4-dicarboxylic acid (trans form)as white crystals (55.0%).

¹H-NMR (CDCl₃, 400 MHz): δ; 0.90 (3H, t, J=6.87 Hz), 1.24-1.40 (12H, m),1.62-1.73 (2H, m), 1.96 (3H, s), 2.27-2.40 (2H, m), 3.44 (1H, d, J=11.4Hz), 3.62 (1H, bdd, J=6.23, 11.9 Hz), 5.06 (1H, d, J=6.57 Hz).

Synthetic Example 25 N-decanoyl-2-methylthiazolidine-2,4-dicarboxylicacid 2,4-diethyl ester

N-Decanoyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl esterobtained by a method similar to that in Synthetic Example 23 wassubjected to ethyl-esterification with ethanol, EDCI HCl and DMAP(dichloromethane solvent) to giveN-decanoyl-2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester(trans form) as a yellow oil (75.3%).

¹H-NMR (CDCl₃, 400 MHz): δ; 0.89 (3H, t, J=6.89 Hz), 1.27 (3H, t, J=7.12Hz), 1.34 (3H, t, J=7.13 Hz), 1.26-1.36 (12H, m), 1.61-1.66 (2H, m),1.94 (3H, s), 2.22-2.31 (2H, m), 3.36 (1H, dd, J=0.53, 11.6 Hz), 3.51(1H, dd, J=6.20, 11.6 Hz), 4.17-4.24 (2H, m), 4.27-4.33 (2H, m), 4.99(1H, d, J=5.82 Hz).

Synthetic Example 26N-hexadecanoyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester

2-Methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester obtained by amethod similar to that in Reference Example was subjected to acylationwith hexadecanoyl chloride in the presence of triethylamine, and themixture was purified by silica gel column chromatography to giveN-hexadecanoyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester(trans form) as white crystals (63.2%).

¹H-NMR (CDCl₃, 400 MH): δ; 0.90 (3H, t, J=6.86 Hz), 1.28 (3H, t, J=7.10Hz), 1.27-1.36 (27 Hz, m), 1.62-1.67 (2H, m), 1.96 (3H, s), 2.27-2.33(2H, m), 3.40 (1H, d, J=11.6 Hz), 3.59 (1H, dd, J=6.27, 11.8 Hz),4.18-4.28 (2H, m), 5.60 (1H, d, J=5.98 Hz).

Synthetic Example 27N-hexadecanoyl-2-methylthiazolidine-2,4-dicarboxylic acid

N-Hexadecanoyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl esterobtained by a method similar to that in Synthetic Example 26 wassubjected to hydrolysis with sodium hydroxide (water-ethanol solvent) togive N-hexadecanoyl-2-methylthiazolidine-2,4-dicarboxylic acid (transform) as a white solid (86.8%).

¹H-NMR (CDCl₃, 400 MHz): δ; 0.88 (3H, t, J=6.86 Hz), 1.23-1.29 (24H, m),1.62-1.67 (2H, m), 1.94 (3H, s), 2.25-2.36 (2H, m), 3.42 (1H, d, J=11.2Hz), 3.59 (1H, bdd, J=6.12, 11.9 Hz), 5.04 (1H, d, J=6.66 Hz).

Synthetic Example 28N-hexadecanoyl-2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethylester

N-Hexadecanoyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl esterobtained by a method similar to that in Synthetic Example 26 wassubjected to ethyl-esterification with ethanol, EDCI HCl and DMAP(dichloromethane solvent) to giveN-hexadecanoyl-2-methylthiazolidine-2,4-dicarboxylic acid 2,4-diethylester (trans form) as a colorless oil (1000).

¹H-NMR (CDCl₃, 400 MHz): δ; 0.88 (3H, t, J=6.86 Hz), 1.26 (3H, t, J=7.07Hz), 1.32 (3H, t, J=7.13 Hz), 1.21-1.34 (24H, m), 1.59-1.65 (2H, m),1.93 (3H, s), 2.22-2.30 (2H, m), 3.35 (1H, dd, J=0.45, 11.6 Hz), 3.53(1H, dd, J=6.19, 11.6 Hz), 4.16-4.22 (2H, m), 4.26-4.32 (2H, m), 4.97(1H, d, J=5.82 Hz).

Synthetic Example 29 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-methyl ester

In the same manner as in Reference Example 2,L-2-methylthiazolidine-2,4-dicarboxylic acid 2-methyl ester wassynthesized from L-cysteine and pyruvic acid methyl ester, and thecompound was subjected to acetylation with acetyl chloride in thepresence of potassium carbonate to giveN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-methyl ester (withthe ratio of cis form:trans form of about 44:56 as confirmed by NMR) asa white solid (80.2%).

¹H-NMR (DMSO-d₆, 400 MHz): δ; trans: 1.75 (3H, s), 2.03 (3H, s), 3.35(1H, dd, J=5.85, 11.7 Hz), 3.41 (1H, dd, J=1.04, 11.6 Hz), 3.61 (3H, s),5.35 (1H, dd, J=0.956, 5.74 Hz).

¹H-NMR (CDCl₃, 400 MHz) δ: trans: 1.95 (3H, s), 2.19 (3H, s), 3.49 (1H,d, J=11.6 Hz), 3.58 (1H, dd, J=6.74, 12.2 Hz), 3.76 (3H, s), 5.01 (1H,d, J=5.80 Hz). cis: 2.01 (3H, s), 2.17 (3H, s), 3.49 (1H, dd, J=1.68,12.3 Hz), 3.72 (1H, dd, J=6.74, 12.2 Hz), 3.95 (3H, s), 5.00 (1H, dd,J=1.68, 6.64 Hz).

Synthetic Example 30 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl 4-methyl ester

N-Acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl esterobtained by a method similar to that in Synthetic Example 7 wassubjected to methyl-esterification with methanol, EDCI HCl and DMAP togive N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl4-methyl ester (with the ratio of cis form:trans form of about 40:60 asconfirmed by NMR) as a colorless oil (88.6%).

¹H-NMR (CDCl₃, 400 MHz): δ; trans: 1.28 (3H, t, J=7.12 Hz), 1.94 (3H,s), 2.13 (3H, s), 3.37 (1H, dd, J=0.558, 11.7 Hz), 3.57 (1H, dd, J=6.19,11.7 Hz), 4.17-4.26 (2H, m), 4.97 (1H, d, J=5.93 Hz). cis: 1.28 (3H, t,J=7.12 Hz), 1.96 (3H, s), 2.17 (3H, s), 3.50 (1H, dd, J=6.03, 11.8 Hz),3.62 (1H, dd, J=1.78, 11.8 Hz), 3.85 (3H, s), 4.17-4.26 (2H, m), 4.88(1H, dd, J=1.77, 6.00 Hz).

Synthetic Example 31 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester 4-glycine methyl ester amide

N-Acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl esterobtained by a method similar to that in Synthetic Example 7 and glycinemethyl ester hydrochloride were subjected to condensation with EDCI HCl,HOBt.H₂O, and triethylamine to giveN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester4-glycine methyl ester amide (with the ratio of cis form:trans form ofabout 52:48 as confirmed by NMR) as a pale-yellow oil (93.7%).

¹H-NMR (CDCl₃, 400 MHz): δ; trans: 1.36 (3H, t, J=7.14 Hz), 1.99 (3H,s), 2.23 (3H, s), 3.44 (1H, dd, J=1.09, 12.3 Hz), 3.70 (1H, dd, J=7.03,12.3 Hz), 3.76 (3H, s), 4.14-4.35 (4H, m), 4.84 (1H, dd, J=1.02, 7.00Hz), 9.09 (1H, bs). cis: 1.30 (3H, t, J=7.12 Hz), 2.07 (3H, s), 2.21(3H, s), 3.36 (1H, d, J=11.9 Hz), 3.62 (1H, dd, J=6.97, 11.9 Hz), 3.81(3H, s), 4.14-4.35 (4H, m), 4.90 (1H, d, J=6.76 Hz), 6.89 (1H, bs).

Synthetic Example 32 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester 4-alanine methyl ester amide

N-Acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl esterobtained by a method similar to that in Synthetic Example 7 andL-alanine methyl ester hydrochloride were subjected to condensation withEDCI HCl, HOBt.H₂O, and triethylamine to giveN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester4-glycine methyl ester amide (with the ratio of cis form:trans form ofabout 49:51 as confirmed by NMR) as a pale-yellow oil (1000).

¹H-NMR (CDCl₃, 400 MHz): δ; trans: 1.35 (3H, t, J=7.13 Hz), 1.48 (3H, d,J=7.20 Hz), 1.99 (3H, s), 2.24 (3H, s), 3.41 (1H, dd, J=0.88, 12.2 Hz),3.67 (1H, dd, J=6.95, 12.2 Hz), 3.74 (3H, s), 4.19-4.24 (2H, m),4.52-4.60 (1H, m), 4.80 (1H, dd, J=0.81, 6.89 Hz), 9.00 (1H, bs). cis:1.29 (3H, t, J=7.12 Hz), 1.48 (3H, d, J=7.36), 2.02 (3H, s), 2.21 (3H,s), 3.35 (1H, d, J=11.9 Hz), 3.60 (1H, dd, J=6.93, 11.9 Hz), 3.78 (3H,s), 4.30-4.36 (2H, m), 4.62-4.68 (1H, m), 4.85 (1H, d, J=6.64 Hz), 6.83(1H, bs).

Synthetic Example 33 N-acetylthiazolidine-2,4-dicarboxylic acid 2-ethylester

L-Cysteine (60.4 g, 0.50 mmol) and ethyl glyoxylate (polymer, 47%toluene solution, 50.9 g, 0.234 mol) were added to water (150 ml), andthe mixture was stirred at room temperature for 50 hours. The obtainedsolution was concentrated under reduced pressure, and the precipitatedsolid was collected by filtration. The obtained white solid (about 40 g)was suspended in water (100 ml), and the suspension was stirred for 16hours at slurry state. The white crystals were collected by filtration,and dried under reduced pressure to give thiazolidine-2,4-dicarboxylicacid 2-ethyl ester as a white solid (30.08 g).

Thiazolidine-2,4-dicarboxylic acid 2-ethyl ester (1.0 g, 4.89 mmol) wassubjected to acylation with acetyl chloride (0.52 ml, 7.31 mmol) in thepresence of triethylamine (1.02 ml, 7.33 mmol) to giveN-acetylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (with the ratioof two kinds of stereoisomers of about 37:63 as confirmed by NMR) as anamorphous solid (1.19 g).

¹H-NMR (CDCl₃, 400 MHz): δ; isomer A: 1.29 (3H, t, J=7.10 Hz), 1.33 (3H,t, J=6.88 Hz), 2.18 (3H, s), 3.44 (1H, d, J=11.7 Hz), 3.68 (1H, dd,J=6.51, 12.0 Hz), 4.19-4.25 (2H, m), 4.94 (1H, d, J=6.09 Hz), 5.36 (1H,s). isomer B: 2.10 (3H, s), 3.33 (1H, dd, J=0.412, 12.2 Hz), 3.57 (1H,dd, J=7.18, 12.3 Hz), 4.19-4.32 (2H, m), 5.18 (1H, d, J=6.80 Hz), 5.27(1H, s).

Synthetic Example 34 N-decanoylthiazolidine-2,4-dicarboxylic acid2-ethyl ester

N-Acetylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester obtained by amethod similar to that in Synthetic Example 33 was subjected toacylation with decanoyl chloride in the presence of triethylamine togive N-decanoylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (withthe ratio of two kinds of stereoisomers of about 46:54 as confirmed byNMR) as white crystals (61.2%).

¹H-NMR (CDCl₃, 400 MHz): δ; isomer A: 0.88 (3H, t, 7.14 Hz), 1.26-1.34(12H, m), 1.29 (3H, t, J=7.18 Hz), 1.66-1.61 (2H, m), 2.28-2.36 (2H, m),3.42 (1H, d, J=12.0 Hz), 3.68 (1H, dd, J=6.52, 12.0 Hz), 4.21 (2H, q,J=7.11 Hz), 4.96 (1H, d, J=6.23 Hz), 5.36 (1H, s). isomer B: 0.88 (3H,t, 7.14 Hz), 1.26-1.34 (12H, m), 1.32 (3H, t, J=7.19 Hz), 1.61-1.66 (2H,m), 2.09-2.17 (1H, m), 2.28-2.36 (1H, m), 3.36 (1H, d, J=12.2 Hz), 3.54(1H, dd, J=7.13, 12.2 Hz), 4.25-4.31 (2H, m), 5.18 (1H, d, J=6.84 Hz),5.25 (1H, s).

Synthetic Example 35 N-decanoylthiazolidine-2,4-dicarboxylic acid

N-Decanoylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester obtained by amethod similar to that in Synthetic Example 34 was subjected tohydrolysis with sodium hydroxide (water-ethanol solvent) to giveN-decanoylthiazolidine-2,4-dicarboxylic acid (with the ratio of twokinds of stereoisomers of about 24:76 as confirmed by NMR) as a whitesolid (79.1%).

¹H-NMR (CDCl₃, 400 MHz): δ; isomer A: 0.86 (3H, t, 6.84 Hz), 1.20-1.32(12H, m), 1.45-1.55 (2H, m), 1.95-2.00 (1H, m), 2.11-2.19 (1H, m), 3.22(1H, d, J=11.8 Hz), 3.47 (1H, dd, J=5.91, 11.8 Hz), 4.84 (1H, d, J=6.96Hz), 5.55 (1H, s). isomer B: 0.86 (3H, t, 6.84 Hz), 1.20-1.32 (12H, m),1.45-1.55 (2H, m), 5.23 (1H, dd, J=0.920, 5.82 Hz), 2.11-2.19 (1H, m),2.35-2.44 (1H, m), 3.39-3.45 (2H, m), 5.06 (1H, s).

Synthetic Example 36 N-decanoylthiazolidine-2,4-dicarboxylic acid2,4-diethyl ester

N-Decanoylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester obtained by amethod similar to that in Synthetic Example 34 was subjected toethyl-esterification with ethanol, EDCI HCl, and DMAP to giveN-decanoylthiazolidine-2,4-dicarboxylic acid 2,4-diethyl ester (theratio of two kinds of stereoisomers was about 21:79) as a yellow waxsubstance (82.7%).

¹H-NMR (CDCl₃, 400 MHz): δ; isomer A: 0.87 (3H, t, 6.88 Hz), 1.25-1.33(18H, m), 1.63-1.67 (2H, m), 2.24-2.30 (2H, m), 3.37 (1H, dd, J=0.640,11.8 Hz), 3.66 (1H, dd, J=6.44, 11.8 Hz), 4.18-4.24 (4H, m), 4.90 (1H,d, J=5.96 Hz), 5.35 (1H, s). isomer B: 0.87 (3H, t, 6.88 Hz), 1.25-1.33(18H, m), 1.63-1.67 (2H, m), 2.05-2.15 (1H, m), 2.26-2.30 (1H, m), 3.16(1H, dd, J=0.780, 12.2 Hz), 3.58 (1H, dd, J=7.22, 12.2 Hz), 4.25-4.29(4H, m), 5.15 (1H, d, J=6.60 Hz), 5.28 (1H, s).

Synthetic Example 37 N-acetylthiazolidine-2,4-dicarboxylic acid2,4-dimethyl ester

Thiazolidine-2,4-dicarboxylic acid (1.00 g, 5.67 mmol) synthesized fromL-cysteine and glyoxylic acid (aqueous solution) were added to amethanol solution (15 ml) of thionyl chloride (22.6 mmol), and themixture was stirred at room temperature for 16 hours. The reactionmixture was concentrated, and to the residue was added ether. Thecrystals were collected by filtration, washed with ether, and driedunder reduced pressure to give thiazolidine-2,4-dicarboxylic acid2,4-dimethyl ester hydrochloride as crystals (1.29 g, 94.0%).

Thiazolidine-2,4-dicarboxylic acid 2,4-dimethyl ester hydrochloride(0.50 g, 2.07 mmol) was subjected to acylation with acetyl chloride(0.22 ml, 3.09 mmol) in the presence of triethylamine (0.58 ml, 4.17mmol) to give N-acetylthiazolidine-2,4-dicarboxylic acid 2,4-dimethylester (with the ratio of two kinds of stereoisomers of about 49:51 asconfirmed by NMR) as a pale-yellow oil (0.42 g, 83.0%).

¹H-NMR (CDCl₃, 400 MHz): δ; isomer A: 2.17 (3H, s), 3.43 (1H, dd,J=7.02, 11.5 Hz), 3.69 (1H, dd, J=4.62, 11.5 Hz), 3.75 (3H, s), 3.85(3H, s), 4.85 (1H, dd, J=4.64, 7.00 Hz), 5.77 (1H, s). isomer B: 5.36(1H, s), 2.21 (3H, s), 3.34 (1H, dd, J=7.18, 11.5 Hz), 3.52 (1H, dd,J=7.92, 11.5 Hz), 3.78 (3H, s), 3.82 (3H, s), 5.05 (1H, t, J=7.56 Hz).

Synthetic Example 38N-acetyl-2-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]thiazolidine-4-carboxylicacid

L-Cysteine hydrochloride (8.00 g, 45.6 mmol), pyridoxal hydrochloride(8.80 g, 43.25 mmol), and sodium hydrogen carbonate (7.60 g, 90.5 mmol)were added to a mixed solvent of water (60 ml) and ethanol (120 ml), andthe mixture was at stored −20° C. for 2 days. The precipitated solid wascollected by filtration, and dried under reduced pressure to give2-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]thiazolidine-4-carboxylicacid as a pale-yellow solid (10.73 g).

To water (1.06 ml) were added2-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]thiazolidine-4-carboxylicacid (500 mg, 1.85 mmol) and acetic anhydride (1.06 ml, 11.1 mmol), andthe mixture was heated at 80° C. for 1 hour. The reaction mixture wasconcentrated under reduced pressure, to the residue was added toluene (5ml×3), and the mixture was concentrated under reduced pressure to giveN-acetyl-2-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]thiazolidine-4-carboxylicacid as an amorphous solid (0.64 g).

To the above-mentioned solid (75 mg) was added ether, and the mixturewas stirred for a while. The precipitate was collected by filtration,and dried under reduced pressure to giveN-acetyl-2-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]thiazolidine-4-carboxylicacid (with the ratio of two kinds of stereoisomers of about 19:81 asconfirmed by NMR)(53 mg) as a powder.

¹H-NMR (CDCl₃, 400 MHz): δ; isomer A: 2.29 (3H, s), 3.24 (1H, dd,J=2.49, 10.6 Hz), 3.39 (1H, dd, J=4.52, 10.7 Hz), 4.43 (2H, dd, J=12.74,15.4 Hz), 4.49 (1H, dd, J=2.20, 6.51 Hz), 6.05 (1H, s), 7.78 (1H, s).isomer B: 2.32 (3H, s), 3.15 (1H, dd, J=8.38, 10.4 Hz), 3.36 (1H, dd,J=6.82, 10.4 Hz), 4.02 (1H, t, J=5.57 Hz), 4.46 (2H, dd, J=6.80, 13.1Hz), 5.88 (1H, s), 7.81 (1H, s).

Synthetic Example 39N-acetyl-2-(1,2,3,4,5-pentahydroxypentyl)thiazolidine-4-carboxylic acidmethyl ester

Under an argon atmosphere, L-cysteine (2.42 g, 20.0 mmol), D-galactose(3.60 g, 20.0 mmol), and pyridine (0.40 ml, 5.0 mmol) were added towater (340 ml), and the solution was heated at 65° C. for 1 hour, andleft standing at room temperature for 2 hours. The precipitated solidwas collected by filtration, and dried under reduced pressure to give2-(1,2,3,4,5-pentahydroxypentyl)thiazolidine-4-carboxylic acid (4.70 g)as white crystals.

Under an argon atmosphere, pyridine (28 ml, 346 mmol) was kept at 0° C.,acetic anhydride (20 ml, 212 mmol) and2-(1,2,3,4,5-pentahydroxypentyl)thiazolidine-4-carboxylic acid (2.0 g,7.06 mmol) were added thereto, and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was concentrated underreduced pressure, to the residue was added ethanol (20 ml), and themixture was stirred. The precipitated solid was collected by filtration,and dried under reduced pressure to give8-acetyl-4-[1,2,3,4-tetrakis(acetoxy)butyl]-3-oxa-6-thia-8-azabicyclo[3.2.1]octan-2-oneas white crystals (2.49 g).

The obtained white crystals (1.0 g, 2.10 mmol) were dissolved inmethanol, and triethylamine (2.1 ml, 15.12 mmol) was added thereto. Thereaction mixture was stirred at room temperature for 16 hours, andconcentrated under reduced pressure. To the residue were added methanoland water, the mixture was stirred, and the precipitate was collected byfiltration, and dried under reduced pressure to giveN-acetyl-2-(1,2,3,4,5-pentahydroxypentyl)thiazolidine-4-carboxylic acidmethyl ester as white crystals (627 mg).

¹H-NMR (D₂O, 400 MHz) δ; 2.23 (3H, s), 3.24 (1H, dd, J=9.16, 11.72 Hz),3.43 (1H, dd, J=8.36, 12.36 Hz), 3.61-3.65 (3H, m), 3.72 (3H, s),3.84-3.95 (3H, m), 4.91 (1H, t, J=8.68 Hz), 5.28 (1H, d, J=10.2 Hz).ESI-MS [M+H]⁺=340.1, [M+Na]⁺=362.0.

Synthetic Example 40N-acetyl-2-(1,2,3,4,5-pentahydroxypentyl)thiazolidine-4-carboxylic acid

8-Acetyl-4-[1,2,3,4-tetrakis(acetoxy)butyl]-3-oxa-6-this-8-azabicyclo[3.2.1]octan-2-one(202 mg, 0.42 mmol) obtained as an intermediate in Synthetic Example 39was dissolved in a mixed solvent of methanol (1.5 ml) and water (1 ml),and 2N NaOH (0.84 ml) was added thereto. The reaction mixture wasstirred for 16 hours, and the pH of the reaction mixture was adjusted to3 with amberlite IR120B H AG. The amberlite IR120B H AG was removed byfiltration, and the filtrate was concentrated under reduced pressure. Asmall amount of methanol was added thereto, and then ether was addedthereto. The precipitated crystals were collected by filtration, anddried under reduced pressure to giveN-acetyl-2-(1,2,3,4,5-pentahydroxypentyl)thiazolidine-4-carboxylic acidas white crystals (70 mg).

¹H-NMR (D₂O, 400 MHz) δ; 2.22 (3H, s), 3.25 (1H, t, J=4.72 Hz),3.39-3.51 (1H, m), 3.57-3.64 (3H, m), 3.80-3.91 (3H, m), 4.84 (1H, t,J=8.80 Hz), 5.28 (1H, d, J=10.1 Hz). ESI-MS [M+Na]⁺=348.0, [M−H]⁻=323.9.

Synthetic Example 41 N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid2-ethyl ester

L-2-Methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (2.00 g, 9.13mmol) obtained by a method similar to that in Reference Example 2 wasdissolved in dichloromethane (19 ml), and the solution was kept at 0° C.To the reaction mixture was added potassium carbonate (2.54 g, 18.4mmol), and acetyl chloride (0.97 ml, 13.7 mmol) was added dropwisethereto. The reaction temperature was allowed to gradually rise, and themixture was stirred at room temperature for 16 hours. To the reactionmixture was added 5% aqueous citric acid (30 ml), and the mixture wasextracted with dichloromethane (20 ml×2). The dichloromethane layer waswashed with water (10 ml×2) and saturated brine (10 ml×2), and driedover anhydrous magnesium sulfate. The magnesium sulfate was removed byfiltration, and the filtrate was concentrated under reduced pressure togive a colorless oil. To the oil was added a small amount of n-hexane.The oil became solidified. The crystals were collected by filtration,washed with n-hexane, and dried under reduced pressure to giveN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (withthe ratio of cis form:trans form of 96:4 as confirmed by HPLC) ascolorless crystals (0.847 g). The melting point of the obtained crystalwas measured using digital melting point measuring apparatus IA9100manufactured by Electrothermal to be 101° C. to 105° C.

¹H-NMR (CDCl₃, 400 MHz): δ: cis: 1.39 (3H, t, J=7.13 Hz), 1.95 (3H, s),2.16 (3H, s), 3.47 (1H, dd, J=1.66, 12.2 Hz), 3.72 (1H, dd, J=6.79, 12.2Hz), 4.33-4.48 (2H, m), 4.98 (1H, dd, J=1.68, 6.78 Hz).

Comparison Synthetic Example 1 Synthesis ofN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid according to themethod described in J. Biological Chem., (1937) 121 539-48

Acetic anhydride (4.5 ml, 47.1 mmol) was kept at 0° C.,2-methylthiazolidine-2,4-dicarboxylic acid (3.0 g, 15.7 mmol) obtainedby a method similar to that in Reference Example 1 and pyridine (3.8 ml,47.1 mmol) were added thereto, and the reaction mixture was stirred atroom temperature for 4 hours. To the reaction mixture was added 2N HCl(25 ml), and the mixture was extracted with ethyl acetate (100 ml). Theethyl acetate layer was washed with saturated brine (20 ml), and driedover anhydrous magnesium sulfate. The magnesium sulfate was removed byfiltration, and the filtrate was concentrated under reduced pressure. Amixture of cis form and trans form ofN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid andN-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid anhydride wasconfirmed by measurement of the residue by ¹H-NMR.

Experimental Example 1 Time-course Stability Test at 70° C.

A time-course stability test was performed using N-Ac-CP2Et obtained inSynthetic Example 1 and N-Ac-CP obtained in Synthetic Example 13 in a 25mM phosphate buffer at pH 4, 5, 6, and 7 and 70° C. The test wasperformed for 4 days. The results are shown in FIGS. 1 to 4. Ascomparison targets, CP obtained in Reference Example 1, and CP2Etobtained in Reference Example 2 were used. For the time-course stabilitytest, HPLC; (pump) HITACHI L-7100, (Autosampler) HITACHI L-2200, and(detector) HITACHI L-4000 were used.

As an index of a time-course stability test at 70° C., the area value ofa target substance after time course changes relative to the area valueof the target substance on day 0 after start of the stability test wascalculated in % on an HPLC chart and used as a residual ratio.

HPLC Analysis Conditions

Conditions-1

-   detector: ultraviolet absorption spectrophotometer (measurement    wavelength; 210 nm)-   column: Inertsil ODS (GL Sciences) (particle size 3 μm, inner    diameter 4.6 mm, length 250 mm)-   eluent: 4 mL/L aqueous phosphoric acid solution:methanol=3:1 (v/v)-   flow rate: 0.8 mL/minute-   column temperature: 50° C.-   sample concentration: 100 mg/dL-   injection volume: 20 μL-   retention time (minute): CP: 4.6, 4.8 (diastereomer mixture),    N-Ac-CP: 8.0    Conditions-2-   detector: ultraviolet absorption spectrophotometer (measurement    wavelength; 210 nm)-   column: Inertsil ODS-3 (High Pressure type, GL Sciences) (particle    size 3 μm, inner diameter 4.6 mm, length 250 mm)-   eluent: A: 0.05M KH₂PO₄ (adjusted to pH2 with 85% H₃PO₄), B: MeOH-   gradient conditions: 0 to 5 minute: A=100, −25 minute: A:B=50:50,    −35 minute: A:B=50:50, −40 minute: A=100, −45 min: A=100-   flow rate: 0.8 mL/minute-   column temperature: 30° C.-   sample concentration: 25-50 mg/dL-   injection volume: 20 μL-   retention time (minute): N-Ac-CP: 21.7, CP2Et: 29.6, 29.8    (diastereomer mixture), N-Ac-CP2Et: 31.2

From FIGS. 1 to 4, it has been found that the cysteine derivative of thepresent invention (N-Ac-CP2Et, N-Ac-CP) shows preservation stabilitybetter than CP and CP2Et, and is a highly useful compound that reachesthe practicalization level for cosmetics and the like.

Experimental Example 2 Time-course Stability Test at 70° C.

A time-course stability test was performed using about 1:1 mixture (20mg/20 ml) of cis form-trans form of N-Ac-CP2Et obtained in SyntheticExample 7 in a 25 mM phosphate buffer at pH 4, 5, 6, and 7 and 70° C. inthe same manner as in Examples Experimental Example 1. The test wasperformed for 5 days. As an index of a time-course stability test at 70°C., the area value of a target substance 5 days after start of thestability test relative to the area value of the target substance on day0 after start of the stability test was calculated in % on an HPLC chartand used as a residual ratio. The results are shown in Table 1.

-   Detector: ultraviolet absorption spectrophotometer (measurement    wavelength; 210 nm)-   Column: Inertsil ODS-3 (High Pressure type, GL Sciences) (particle    size 3 μm, inner diameter 4.6 mm, length 250 mm)-   eluent: A: 0.05M KH₂PO₄ (adjusted to pH2 with 85% H₃PO₄), B: MeOH-   gradient conditions: 0-5 minute: A=100, −25 minute: A:B=50:50, −35    minute: A:B=50:50, −40 minute: A=100, −45 minute: A=100-   flow rate: 0.8 mL/minute-   column temperature: 30° C.-   sample concentration: 25-50 mg/dL-   injection volume: 20 μL-   retention time (minute): N-Ac-CP2Et (cis form): 31.9, N-Ac-CP2Et    (trans form): 33.9

TABLE 1 N-Ac-CP2Et (cis form) N-Ac-CP2Et (trans form) of SyntheticExample 7 of Synthetic Example 7 residual 69.9 95.8 ratio (%) at pH 4residual 93.5 99.8 ratio (%) at pH 5 residual 96.9 >99.9 ratio (%) at pH6 residual >99.9 >99.9 ratio (%) at pH 7

From Table 1, it has been found that both cis form and trans form ofN-Ac-CP2Et, which is the cysteine derivative of the present invention,show good preservation stability. By comparison of the cis form andtrans form, it has been found that the trans form is more superior inthe stability under particularly acidic conditions (particularly, pH 5or below).

Experimental Example 3 Odor Test

1 wt % Aqueous solutions (pH 4 or 7) of the cysteine derivatives ofSynthetic Examples 10, 33, and 37, CP obtained in Reference Example 1,and CP2Et obtained in Reference Example 2 were prepared, tightly sealed,and preserved in a thermostatic tank at 70° C. for 4 days or 6 days.Each sample was taken out from the thermostatic tank, immediatelythereafter smelled for odor by 6 panelists, and evaluated by thefollowing criteria.

-   3 points: no sulfur odor was detected at all-   2 points: slight sulfur odor was detected-   1 point: sulfur odor was detected-   0 point: strong sulfur odor was detected

The results of the 6 panelists were totaled, and the total points wereevaluated as ⊚: not less than 15 points, ◯: not less than 10 points andless than 15 points, Δ: not less than 5 points and less than 10 points,x: not less than 0 point and less than 5 points. The results are shownin Table 2.

TABLE 2 cysteine cysteine cysteine derivative derivative derivative ofof of Synthetic Synthetic Synthetic Example 10 Example 33 Example 37CP2Et CP evaluation ◯ (10 ⊙ (16 ◯ (10 X (3 X (6 at pH 4 points) points)points) points) points) (day 4) evaluation Δ (8 ⊙ (15 Δ (9 X (1 Δ (7 atpH 4 points) points) points) points) points) (day 6) evaluation ⊙ (18 ⊙(18 ◯ (12 X (3 — (*) at pH 7 points) points) points) points) (day 4)evaluation ⊙ (17 ⊙ (17 Δ (9 X (1 — (*) at pH 7 points) points) points)point) (day 6) * Since precipitate considered to be cysteine wasconfirmed, odor evaluation was not performed.

It has been found that the cysteine derivative of the present inventionshows less odor and less sulfur odor due to decomposition and goodpreservation stability, and therefore, is a highly useful compound thatreaches the practicalization level for cosmetics and the like.

Experimental Example 4 Eumelanin Production Suppression Test

B16 melanoma was cultured in DMEM (Dulbecco's Modified Eagle Medium)(high glucose, containing 10% serum). Confluent cells were detached withtrypsin, and plated on a 96 well plate. After cell adhesion to the platethe next day, the medium was changed to DMEM added with each evaluationsample (control (no sample addition), cysteine derivatives of eachSynthetic Example) at a predetermined evaluation concentration (dilutedfrom 10 mM according to sample), and the cells were cultured for 3 days.The 96 well plate was shaken for 5 minutes in a plateshaker, and theabsorbance of the medium at 450 nm was measured by a microplatereader.The absorbance after 3 days from the addition of a predeterminedconcentration of each sample was shown in relative percentage to themeasured value (absorbance) of the control (no sample addition) as 100%,and the concentration necessary for suppressing eumelanin production ineach sample by 50% was calculated as 50% melanin production suppressingconcentration relative to the amount of eumelanin in the control as100%. The results are shown in Table 3.

The microplatereader used in this eumelanin production suppression testwas Benchmark microplatereader, manufactured by BIORAD.

TABLE 3 50% melanin production suppressing concentration cysteinederivative of 4538 μM Synthetic Example 1 cysteine derivative of 5474 μMSynthetic Example 13 cysteine derivative of 2606 μM Synthetic Example 19cysteine derivative of 1420 μM Synthetic Example 20

It was found that the cysteine derivative of the present invention hasan effect of suppressing the amount of eumelanin released from thecells.

INDUSTRIAL APPLICABILITY

It has been determined that the cysteine derivative of the presentinvention is superior in stability, and has less odor and sufficienteumelanin production suppressive effect. As a result, a whitening agent,a fleck improving agent or therapeutic agent, and a winkle improvingagent or therapeutic agent, which have better stability and less odorthan conventional L-cysteine derivatives, can be provided, as well as acosmetic agent or skin external preparation containing such agent, whichis superior in long-term preservation stability.

Where a numerical limit or range is stated herein, the endpoints areincluded. Also, all values and subranges within a numerical limit orrange are specifically included as if explicitly written out.

As used herein the words “a” and “an” and the like carry the meaning of“one or more.”

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

All patents and other references mentioned above are incorporated infull herein by this reference, the same as if set forth at length.

The invention claimed is:
 1. A cysteine compound represented by formula(I):

wherein X and Y are each independently OR¹ or NHR² wherein R¹ and R² areeach independently a hydrogen atom or a C₁₋₂₂ alkyl group or X and Ytogether are —O—; Z is a hydrogen or C₁₋₂₂ alkyl group; provided thatwhen Z is a hydrogen atom, at least one of (i) and (ii) is satisfied;(i) X is not methoxy, or (ii) Y is not hydroxy; and W is a C₁₋₂₂ alkylgroup, a C₁₋₂₂ alkoxy group or a C₁₋₂₂ alkylamino group, or a saltthereof; and provided that said compound or a salt thereof is not:N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid or a salt thereof,N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid anhydride or a saltthereof, or N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethylester or a salt thereof.
 2. A cysteine compound or salt thereofaccording to claim 1, which is in the trans form.
 3. The cysteinecompound or salt thereof according to claim 1, wherein Z is a C₁₋₂₂alkyl group.
 4. The cysteine compound or salt thereof according to claim1, wherein Z is a hydrogen atom.
 5. The cysteine compound or saltthereof according to claim 4, wherein X is not methoxy.
 6. The cysteinecompound or salt thereof according to claim 4, wherein Y is not hydroxy.7. The cysteine compound or salt thereof according to claim 4, wherein Xis not methoxy and Y is not hydroxy.
 8. A method of producing a cysteinecompound according to claim 1, said method comprising: reacting acompound represented by formula (IV):

wherein each symbol is as defined in claim 1, with: (a) a compoundrepresented by formula (V):

wherein A is a halogen atom; and W is as defined in claim 1, or (b) acompound represented by formula (V′):

wherein W is as defined in claim
 1. 9. A method of selectively producinga trans form of a cysteine compound according to claim 1, represented byformula (I′):

wherein Y″ is a C₁₋₂₂ alkoxy group; Z″ is a C₁₋₂₂ alkyl group; and W isa C₁₋₂₂ alkyl group, a C₁₋₂₂ alkoxy group or a C₁₋₂₂ alkylamino group,or a salt thereof, said method comprising: reacting a compoundrepresented by formula (IV′):

wherein each symbol is as defined above, with: (a) a compoundrepresented by formula (V):

wherein A is a halogen atom; and W is as defined above, in the presenceof an organic base, or (b) a compound represented by formula (V′):

wherein W is as defined above, in the absence of a base.